Dana-Farber Research News, 9.1.2021

This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors. 
Cancer Cell
Labaki C, Bakouny Z, Schmidt A, Lipsitz SR, Rebbeck TR, Trinh QD, Choueiri TK
Following the pandemic onset, a dramatic decrease in the number of cancer screening tests and ensuing diagnoses was observed. The consequent delays in diagnosis are expected to result in adverse oncologic outcomes. It is unknown to what extent screening pathways adapted during the pandemic, enabling the recovery of missed diagnoses.
Cancer Discovery
Kumar S, Zeng Z, Bagati A, Tay RE, Ito Y, Abderazzaq F, Hatchi E, Jiang P, Cartwright ANR,
Olawoyin O, Mathewson ND, Pyrdol JW, Li MZ, Doench JG, Booker MA, Tolstorukov MY, Elledge SJ, Liu XS, Wucherpfennig KW
A number of cancer drugs activate innate immune pathways in tumor cells but unfortunately also compromise antitumor immune function. We discovered that inhibition of CARM1, an epigenetic enzyme and cotranscriptional activator, elicited beneficial antitumor activity in both cytotoxic T cells and tumor cells. In T cells, Carm1 inactivation substantially enhanced their antitumor function and preserved memory-like populations required for sustained antitumor immunity. In tumor cells, Carm1 inactivation induced a potent type 1 interferon response that sensitized resistant tumors to cytotoxic T cells. Substantially increased numbers of dendritic cells, CD8 T cells, and natural killer cells were present in Carm1-deficient tumors, and infiltrating CD8 T cells expressed low levels of exhaustion markers. Targeting of CARM1 with a small molecule elicited potent antitumor immunity and sensitized resistant tumors to checkpoint blockade. Targeting of this cotranscriptional regulator thus offers an opportunity to enhance immune function while simultaneously sensitizing resistant tumor cells to immune attack. SIGNIFICANCE: Resistance to cancer immunotherapy remains a major challenge. Targeting of CARM1 enables immunotherapy of resistant tumors by enhancing T-cell functionality and preserving memory-like T-cell populations within tumors. CARM1 inhibition also sensitizes resistant tumor cells to immune attack by inducing a tumor cell-intrinsic type 1 interferon response.This article is highlighted in the In This Issue feature, p. 1861.
Cancer Discovery
Mahadevan NR, Knelson EH, Wolff JO, Vajdi A, Saigi M, Campisi M, Hong D, Thai TC, Piel B, Han S, Reinhold BB, Duke-Cohan JS, Poitras MJ, Taus LJ, Lizotte PH, Portell A, Quadros V, Santucci AD, Kitajima S, Akitsu A, Reardon B, Gokhale PC, Paweletz CP, Awad MM, Van Allen EM, Hong F,
Sholl LM, Tolstorukov MY, Pfaff K, Jänne PA, Rodig S, Reinherz EL, Oser MG, Barbie DA
Small cell lung carcinoma (SCLC) is highly mutated, yet durable response to immune checkpoint blockade (ICB) is rare. SCLC also exhibits cellular plasticity, which could influence its immunobiology. Here we discover that a distinct subset of SCLC uniquely upregulates MHC I, enriching for durable ICB benefit. In vitro modeling confirms epigenetic recovery of MHC I in SCLC following loss of neuroendocrine differentiation, which tracks with derepression of STING. Transient EZH2 inhibition expands these nonneuroendocrine cells, which display intrinsic innate immune signaling and basally restored antigen presentation. Consistent with these findings, murine nonneuroendocrine SCLC tumors are rejected in a syngeneic model, with clonal expansion of immunodominant effector CD8 T cells. Therapeutically, EZH2 inhibition followed by STING agonism enhances T-cell recognition and rejection of SCLC in mice. Together, these data identify MHC I as a novel biomarker of SCLC immune responsiveness and suggest novel immunotherapeutic approaches to co-opt SCLC's intrinsic immunogenicity. SIGNIFICANCE: SCLC is poorly immunogenic, displaying modest ICB responsiveness with rare durable activity. In profiling its plasticity, we uncover intrinsically immunogenic MHC Ihi subpopulations of nonneuroendocrine SCLC associated with durable ICB benefit. We also find that combined EZH2 inhibition and STING agonism uncovers this cell state, priming cells for immune rejection.This article is highlighted in the In This Issue feature, p. 1861.
Cell Stem Cell
Shivdasani RA
Mutant oncogenes could enable clonal dominance by cell-intrinsic means or by suppressing nearby wild-type stem cells. Reporting recently in Nature, three groups demonstrate potent neighborhood effects, both within intestinal crypts (Flanagan et al., 2021; van Neerven et al., 2021) and across crypts through intermediary sub-epithelial trophocytes (Yum et al., 2021).
Journal of Clinical Oncology
Köhler J, Jänne PA
Insertions in exon 20 of the epidermal growth factor (EGF) receptor (EGFR Ex20ins) represent the third and most common type of activating EGFR mutations in non-small-cell lung cancer (NSCLC). With some geographical variation, they are detected in up to 4% of all advanced NSCLC and in 4%-12% of EGFR mutation-positive NSCLC. EGFR Ex20ins are more common in tumors amoung never smokers, but unlnike common Exon19 deletions or Exon21 L858R poing mutations, most of the Ex20ins mutations (except for EGFR A763_Y764FQEA) exhibit de novo resistance to the currently approved first-line EGFR tyrosine kinase inhibitors (TKIs): erlotinib, gefitinib, afatinib, and Osimertinib. Therefore, chemotherapy represents the mainstay treatment option. Mechanisms of TKI resistance are multifactorial including steric hinderance, similar TKI affinities to Exon20ins-mutation EGFR, and unchanged ATP binding of mutant compared with wild-type EGFR.
Journal of Clinical Oncology
Richardson PG, Laubach JP
PURPOSE: The double-blind, placebo-controlled, phase III TOURMALINE-MM1 study demonstrated a statistically significant improvement in progression-free survival with ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd in patients with relapsed or refractory multiple myeloma. We report the final analyses for overall survival (OS).
PATIENTS AND METHODS: Patients were randomly assigned to ixazomib-Rd (n = 360) or placebo-Rd (n = 362), stratified by number of prior therapies (1 v 2 or 3), previous proteasome inhibitor (PI) exposure (yes v no), and International Staging System disease stage (I or II v III). OS (intent-to-treat population) was a key secondary end point.
RESULTS: With a median follow-up of 85 months, median OS with ixazomib-Rd versus placebo-Rd was 53.6 versus 51.6 months (hazard ratio, 0.939; P = .495). Lower hazard ratios, indicating larger magnitude of OS benefit with ixazomib-Rd versus placebo-Rd, were seen in predefined subgroups: refractory to any (0.794) or last (0.742) treatment line; age > 65-75 years (0.757); International Staging System stage III (0.779); 2/3 prior therapies (0.845); high-risk cytogenetics (0.870); and high-risk cytogenetics and/or 1q21 amplification (0.862). Following ixazomib-Rd versus placebo-Rd, 71.7% versus 69.9% of patients received 1 anticancer therapy, of whom 24.7% versus 33.9% received daratumumab and 71.8% versus 76.9% received PIs (next-line therapy: 47.5% v 55.8%). Rates of new primary malignancies were similar with ixazomib-Rd (10.3%) and placebo-Rd (11.9%). There were no new or additional safety concerns.
CONCLUSION: Median OS values in both arms were the longest reported in phase III studies of Rd-based triplets in relapsed or refractory multiple myeloma at the time of this analysis; progression-free survival benefit with ixazomib-Rd versus placebo-Rd did not translate into a statistically significant OS benefit on intent-to-treat analysis. OS benefit was greater in subgroups with adverse prognostic factors. OS interpretation was confounded by imbalances in subsequent therapies received, especially PIs and daratumumab.
Journal of the National Cancer Institute
Fillmore NR, DuMontier C, Yildirim C, La J, Cheng D, Cirstea D, Abel GA, Gaziano JM, Kim DH, Munshi NC, Driver JA
BACKGROUND: Traditional count-based measures of comorbidity are unlikely to capture the complexity of multiple chronic conditions (multimorbidity) in older adults with cancer. We aimed to define patterns of multimorbidity and their impact in older United States veterans with multiple myeloma (MM).
METHODS: We measured 66 chronic conditions in 5076 veterans aged 65 years and older newly treated for MM in the national Veterans Affairs health-care system from 2004 to 2017. Latent class analysis was used to identify patterns of multimorbidity among these conditions. These patterns were then assessed for their association with overall survival, our primary outcome. Secondary outcomes included emergency department visits and hospitalizations.
RESULTS: Five patterns of multimorbidity emerged from the latent class analysis, and survival varied across these patterns (log-rank 2-sided P <.001). Older veterans with cardiovascular and metabolic disease (30.9%, hazard ratio [HR] = 1.33, 95% confidence interval [CI] = 1.21 to 1.45), psychiatric and substance use disorders (9.7%, HR = 1.58, 95% CI = 1.39 to 1.79), chronic lung disease (15.9%, HR = 1.69, 95% CI = 1.53 to 1.87), and multisystem impairment (13.8%, HR = 2.25, 95% CI = 2.03 to 2.50) had higher mortality compared with veterans with minimal comorbidity (29.7%, reference). Associations with mortality were maintained after adjustment for sociodemographic variables, measures of disease risk, and the count-based Charlson Comorbidity Index. Multimorbidity patterns were also associated with emergency department visits and hospitalizations.
CONCLUSIONS: Our findings demonstrate the need to move beyond count-based
measures of comorbidity and consider cancer in the context of multiple chronic conditions.
Oliveira G, Stromhaug K, Klaeger S, Kula T, Frederick DT, Le PM, Forman J, Huang T, Li S, Zhang W, Cieri N, Clauser KR, Shukla SA, Neuberg D, Carr SA, Fritsch EF, Hacohen N, Sade-Feldman M,
Livak KJ, Boland GM, Ott PA, Keskin DB, Wu CJ
Interactions between T cell receptors (TCRs) and their cognate tumour antigens are central to antitumour immune responses1-3; however, the relationship between phenotypic characteristics and TCR properties is not well elucidated. Here we show, by linking the antigenic specificity of TCRs and the cellular phenotype of melanoma-infiltrating lymphocytes at single-cell resolution, that tumour specificity shapes the expression state of intratumoural CD8+ T cells. Non-tumour-reactive T cells were enriched for viral specificities and exhibited a non-exhausted memory phenotype, whereas melanoma-reactive lymphocytes predominantly displayed an exhausted state that encompassed diverse levels of differentiation but rarely acquired memory properties. These exhausted phenotypes were observed both among clonotypes specific for public overexpressed melanoma antigens (shared across different tumours) or personal neoantigens (specific for each tumour). The recognition of such tumour antigens was provided by TCRs with avidities inversely related to the abundance of cognate targets in melanoma cells and proportional to the binding affinity of peptide-human leukocyte antigen (HLA) complexes. The persistence of TCR clonotypes in peripheral blood was negatively affected by the level of intratumoural exhaustion, and increased in patients with a poor response to immune checkpoint blockade, consistent with chronic stimulation mediated by residual tumour antigens. By revealing how the quality and quantity of tumour antigens drive the features of T cell responses within the tumour microenvironment, we gain insights into the properties of the anti-melanoma TCR repertoire.
Nature Cell Biology
He YJ, Chowdhury D
Double-strand DNA breaks (DSBs) are repaired by two major mechanistically distinct pathways, homologous recombination (HR) and non-homologous end-joining (NHEJ). The relative contributions of the competing DSB repair pathways differ across cell types and throughout the cell cycle, and this balance is critical for maintaining genomic stability. A decisive factor in the choice between DSB repair pathways is the competition between DNA end protection, which is necessary for NHEJ, and DNA end resection, which is necessary for HR. DSB end resection must be appropriately restricted to S and G2 phases of the cell cycle, as HR requires the presence of an intact sister chromatid. Depletion of NHEJ-promoting factors such as 53BP1 allows DNA end resection in the G1 phase, thereby impairing DSB repair and causing genomic instability. Conversely, loss of BRCA1, an HR protein that is critical for end resection initiation, allows the error-prone NHEJ pathway to dominate throughout the cell cycle, potentially leading to tumourigenesis. Loss of BRCA1 provides a therapeutic opportunity in these tumours, as they become sensitive to inhibitors of the DNA repair protein poly(ADP-ribose) polymerase (PARP) and to platinum-based drugs. Surprisingly, loss of 53BP1 or associated factors (e.g., RIF1, shieldin complex) in BRCA1-depleted tumours renders them insensitive to PARP inhibitors (PARPi), as DNA end resection and the subsequent steps of the HR pathway are restored. Therefore, factors that regulate the processing of DNA ends are crucial for pathway choice and may have tremendous relevance in cancer biology. In this issue of Nature Cell Biology, Zhao, Kim et al. report that ASTE1, a previously uncharacterised XPG family DNA endonuclease, functions as a downstream effector of 53BP1-shieldin in promoting NHEJ, thereby regulating the balance of DSB repair pathways.
Nature Communications
Bloch NB, Prew MS, Levy HR, Walensky LD
BAX is a pro-apoptotic member of the BCL-2 family, which regulates the balance between cellular life and death. During homeostasis, BAX predominantly resides in the cytosol as a latent monomer but, in response to stress, transforms into an oligomeric protein that permeabilizes the mitochondria, leading to apoptosis. Because renegade BAX activation poses a grave risk to the cell, the architecture of BAX must ensure monomeric stability yet enable conformational change upon stress signaling. The specific structural features that afford both stability and dynamic flexibility remain ill-defined and represent a critical control point of BAX regulation. We identify a nexus of interactions involving four residues of the BAX core ?5 helix that are individually essential to maintaining the structure and latency of monomeric BAX and are collectively required for dimeric assembly. The dual yet distinct roles of these residues reveals the intricacy of BAX conformational regulation and opportunities for therapeutic modulation.
Nature Communications
Stamenova EK, Meissner A, Michor F
Precise control of mammalian gene expression is facilitated through epigenetic mechanisms and nuclear organization. In particular, insulated chromosome structures are important for regulatory control, but the phenotypic consequences of their boundary disruption on developmental processes are complex and remain insufficiently understood. Here, we generated deeply sequenced Hi-C data for human pluripotent stem cells (hPSCs) that allowed us to identify CTCF loop domains that have highly conserved boundary CTCF sites and show a notable enrichment of individual developmental regulators. Importantly, perturbation of such a boundary in hPSCs interfered with proper differentiation through deregulated distal enhancer-promoter activity. Finally, we found that germline variations affecting such boundaries are subject to purifying selection and are underrepresented in the human population. Taken together, our findings highlight the importance of developmental gene isolation through chromosomal folding structures as a mechanism to ensure their proper expression.
Nature Genetics
Sheffer M, Lowry E, Borah M, Amara SN, Mader CC, Roth JA, Tsherniak A, Freeman SS, Dashevsky O, Gandolfi S, Bender S, Bryan JG, Zhu C, Wang L, Tariq I, Simoes RM, Dhimolea E, Yu C, Hu Y, Giannakis M, Fraenkel E, Golub T, Romee R, Culhane AC, Mitsiades CS
To systematically define molecular features in human tumor cells that determine their degree of sensitivity to human allogeneic natural killer (NK) cells, we quantified the NK cell responsiveness of hundreds of molecularly annotated 'DNA-barcoded' solid tumor cell lines in multiplexed format and applied genome-scale CRISPR-based gene-editing screens in several solid tumor cell lines, to functionally interrogate which genes in tumor cells regulate the response to NK cells. In these orthogonal studies, NK cell-sensitive tumor cells tend to exhibit 'mesenchymal-like' transcriptional programs; high transcriptional signature for chromatin remodeling complexes; high levels of B7-H6 (NCR3LG1); and low levels of HLA-E/antigen presentation genes. Importantly, transcriptional signatures of NK cell-sensitive tumor cells correlate with immune checkpoint inhibitor (ICI) resistance in clinical samples. This study provides a comprehensive map of mechanisms regulating tumor cell responses to NK cells, with implications for future biomarker-driven applications of NK cell immunotherapies.
Abdominal Radiology
Könik A, Miskin N, Guo Y, Shinagare AB, Qin L
American Journal of Emergency Medicine
Lai L, Sato R, Ouchi K, Landman AB, Zhang HM
Annals of Surgical Oncology
Kantor O, Wang ML, Freedman RA, Chavez-MacGregor M, King TA, Mittendorf EA
Blood Advances
Miller PG, Sperling AS, Brea EJ, Leick MB, Fell GG, Jan M, Gohil SH, Tai YT, Munshi NC, Wu CJ, Neuberg DS, Maus MV, Jacobson C, Gibson CJ, Ebert BL
British Journal of Cancer
Lapidot M, Case AE, Weisberg EL, Meng C, Garg S, Ni W, Hung YP, Carrasco RD, Knott A,
Gokhale PC, Frank DA, Griffin JD, Saladi SV, Bueno R, Sattler M
British Journal of Haematology
Gustine JN, Xu L, Yang G, Liu X, Kofides A, Tsakmaklis N, Munshi M, Demos M, Guerrera ML, Meid K, Patterson CJ, Sarosiek S, Branagan AR, Hunter ZR, Castillo JJ, Treon SP
British Journal of Haematology
Castillo JJ, LaMacchia J, Flynn CA, Sarosiek S, Pozdnyakova O, Treon SP
Breast Cancer Research
Lal JC, Townsend MG, Mehta AK, Oliwa M, Sotayo A, Cheney E, Mittendorf EA, Letai A, Guerriero JL
Breast Cancer Research and Treatment
Zheng Y, Tayob N, Hu J, Isakoff SJ, Faggen MG, Mulvey TM, Sella T, Constantine M, Briccetti FM, Rosenberg S, DeMeo MK, Burstein HJ, Winer EP, Krop IE, Partridge AH, Tolaney SM
Breast Cancer Research and Treatment
Leone JP, Hassett MJ, Graham N, Tayob N, Freedman RA, Tolaney SM, Winer EP, Lin NU
Breast Cancer Research and Treatment
Freedman RA, Lin NU, Tolaney SM, Winer EP, Leone JP
Breast Cancer Research and Treatment
Chipidza FE, Iyer HS, Bellon JR, Elmore SN
Sella T, Poorvu PD, Gelber SI, Peppercorn JM, Come SE, Partridge AH, Rosenberg SM
Cancer Immunology, Immunotherapy
Tyan K, Baginska J, Brainard M, Giobbie-Hurder A, Severgnini M, Manos M, Haq R, Buchbinder EI, Ott PA, Hodi FS, Rahma OE
Cancer Research
Gillani R, Seong BKA, Crowdis J, Conway JR, Dharia NV, Haas BJ, Park J, Dietlein F, He MX, Imamovic A, Ma C, Boehm JS, Vazquez F, Gusev A, Liu D, Janeway KA, McFarland JM, Stegmaier K, Van Allen EM
Cancer Research
Puleo J, Polyak K
Chemical Society Reviews
Chan WC, Sharifzadeh S, Buhrlage SJ, Marto JA
Clinical Cancer Research
Sperling AS, Anderson KC
Clinical Cancer Research
Pappa T, Ahmadi S, Marqusee E, Johnson HL, Nehs MA, Cho NL, Barletta JA, Lorch JH, Doherty GM, Lindeman NI, Alexander EK, Landa I
Kofides A, Hunter ZR, Xu L, Tsakmaklis N, Demos MG, Munshi M, Liu X, Guerrera ML, Leventoff CR, White TP, Flynn CA, Meid K, Patterson CJ, Yang G, Branagan AR, Sarosiek S, Castillo JJ, Treon SP, Gustine JN
Hematology/Oncology Clinics of North America
Brown JR
International Journal of Radiation Oncology, Biology, Physics
Atkins KM, Bitterman DS, Chaunzwa TL, Kozono DE, Baldini EH, Aerts HJWL, Hoffmann U, Nohria A, Mak RH
International Journal of Radiation Oncology, Biology, Physics
Bellon JR
Journal of Biological Chemistry
Huang SC, Vu LV, Yu FH, Nguyen DT, Benz EJ Jr
Journal of Medicinal Chemistry
Nowak RP, Xiong Y, Kirmani N, Kalabathula J, Donovan KA, Eleuteri NA, Yuan JC, Fischer ES
Journal of Pain and Symptom Management
Maloney FL, Hawrusik B, Paquette E, Takahashi K, Downey N, Paladino J, Bernacki RE
Journal of Pain and Symptom Management
Umaretiya P, Wolfe J, Bona K
Journal of Pain and Symptom Management
Chen JJ, Rawal B, Krishnan MS, Hertan LM, Shi DD, Roldan CS, Huynh MA, Spektor A, Balboni TA
Journal of Palliative Medicine
Lakin JR, Gundersen DA, Lindvall C, Tulsky JA, Volandes A
Journal of Urology
Mantia CM, Sonpavde GP
Journal of Urology
Sonpavde GP
Leukemia and Lymphoma
Branagan AR, Lei M, Treon SP, Castillo JJ
Pikman Y, Ocasio-Martinez N, Alexe G, Dimitrov B, Kitara S, Robichaud AL, Conway AS, Ross L, Qi J, Vander Heiden MG, Stegmaier K
Ray A, Du T, Song Y, Buhrlage SJ, Chauhan D, Anderson KC
Molecular Cancer Therapeutics
Nassar AH, Adib E, Jegede OA, Alaiwi SA, Braun DA, Zarei M, Du H, Sonpavde GP
G C Lopez B, Du Z, Korsunsky I, Abdelmoula WM, Dai Y, Stopka SA, Gaglia G, Randall EC,
Regan MS, Basu SS, Clark AR, Supko JG, Raychaudhuri S, Ligon KL, Wen PY, Alexander B, Lee EQ, Santagata S, Agar NYR
Santagata S, Ligon KL
Ugai T, Zhao M, Akimoto N, Shi S, Takashima Y, Zhong R, Lau MC, Haruki K, Arima K, Fujiyoshi K, Langworthy B, Masugi Y, da Silva A, Nosho K, Baba Y, Song M, Chan AT, Wang M, Meyerhardt JA, Giannakis M, Väyrynen JP, Nowak JA, Ogino S
Klein IA, Rosenberg SM, Reynolds KL, Zubiri L, Rosovsky R, Piper-Vallillo AJ, Gao X, Boland G, Bardia A, Gaither R, Freeman H, Kirkner GJ, Rhee C, Klompas M, Baker MA, Wadleigh M, Winer EP, Kotton CN, Partridge AH
Habib AR, Chen R, Magnavita ES, Jaung T, Awad MM, Odejide O, Abel GA
Oral Oncology
Hanna GJ, ONeill A, Cutler JM, Flynn M, Vijaykumar T, Clark JR, Wirth LJ, Lorch JH, Park JC,
Mito JK, Lohr JG, Zon LI, Haddad RI
Radiotherapy and Oncology
Dee EC, Muralidhar V, King MT, Martin NE, D'Amico AV, Mouw KW, Orio PF, Nguyen PL, Leeman JE
Supportive Care in Cancer
Knoerl R, Phillips CS, Berfield J, Woods H, Acosta M, Tanasijevic A, Ligibel J
Urologic Clinics of North America
Berro T, Barrett E, AlDubayan SH
Urologic Oncology
Berry DL, Hong F, Blonquist TM, Halpenny B, Xiong N, Chang P, Hayes JH, Trinh QD
Sha ST, Dee EC, Mossanen M, Zaslowe-Dude C, Royce TJ, Hirsch MS, Preston MA, Nguyen PL, Mouw KW, Muralidhar V