Cancer Immunology Research

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ISSN / EISSN : 2326-6066 / 2326-6074
Total articles ≅ 1,282
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, Chang-Ching Lin, , Joonbeom Bae, Vishal Kandagatla, Dan Ye, , , Saurabh Mendiratta, , et al.
Cancer Immunology Research; https://doi.org/10.1158/2326-6066.cir-21-0826

Abstract:
The MYC oncogene is frequently amplified in triple negative breast cancer (TNBC). Here, we show that MYC suppression induces immune-related hallmark gene set expression and tumor-infiltrating T cells in MYC-hyperactivated TNBCs. Mechanistically, MYC repressed stimulator of interferon genes (STING) expression via direct binding to the STING1 enhancer region, resulting in downregulation of the T-cell chemokines CCL5, CXCL10 and CXCL11. In primary and metastatic TNBC cohorts, tumors with high MYC expression or activity exhibited low STING expression. Using a CRISPR-mediated enhancer perturbation approach, we demonstrated that MYC-driven immune evasion is mediated by STING repression. STING repression induced resistance to PD-L1 blockade in mouse models of TNBC. Finally, a small molecule inhibitor of MYC combined with PD-L1 blockade elicited a durable response in immune-cold TNBC with high MYC expression, suggesting a strategy to restore PD-L1 inhibitor sensitivity in MYC-overexpressing TNBC.
Cancer Immunology Research; https://doi.org/10.1158/2326-6066.cir-22-0315

Abstract:
Immune checkpoint inhibitors have yet to significantly improve outcomes for hormone-dependent estrogen/progesterone receptor–positive breast cancer. To address this issue, there is a need for murine models that more closely mimic hormone receptor–positive breast cancer. In this issue, Gil Del Alcazar and colleagues provide an in-depth characterization of a Nitroso-N-methylurea–induced mammary tumor model in outbred Sprague-Dawley rats that meets these needs as it mimics the heterogeneity for mutational profiles, estrogen receptor expression, and immune evasive mechanisms observed in human breast cancer. See related article by Gil Del Alcazar et al., (1).
Saketh S. Dinavahi, Yu-Chi Chen, Kishore Punnath, , Meenhard Herlyn, , ,
Cancer Immunology Research; https://doi.org/10.1158/2326-6066.cir-21-0587

Abstract:
Immunotherapy has revolutionized cancer treatment. Unfortunately, most tumor types do not respond to immunotherapy due to a lack of immune infiltration or “cold” tumor microenvironment (TME), a contributing factor in treatment failure. Activation of the p53 pathway can increase apoptosis of cancer cells, leading to enhanced antigen presentation, and can stimulate natural killer (NK) cells through expression of stress ligands. Therefore, modulation of the p53 pathway in cancer cells with wild-type TP53 has the potential to enhance tumor immunogenicity to NK cells, produce an inflammatory TME, and ultimately lead to tumor regression. In this study, we report simultaneous targeting of the AKT/WEE1 pathways is a novel and tolerable approach to synergistically induce p53 activation to inhibit tumor development. This approach reduced the growth of melanoma cells and induced plasma membrane surface localization of the ER-resident protein calreticulin, an indicator of immunogenic cell death (ICD). Increase in ICD led to enhanced expression of stress ligands recognized by the activating NK-cell receptor NKG2D, promoting tumor lysis. WEE1/AKT inhibition resulted in recruitment and activation of immune cells, including NK cells, in the TME, triggering an inflammatory cascade that transformed the “cold” TME of B16F10 melanoma into a “hot” TME that responded to anti–programmed cell death protein 1 (anti–PD-1), resulting in complete regression of established tumors. These results suggest that AKT/WEE1 pathway inhibition is a potential approach to broaden the utility of class-leading anti–PD-1 therapies by enhancing p53-mediated, NK cell–dependent tumor inflammation and supports the translation of this novel approach to further improve response rates for metastatic melanoma.
Carlos R. Gil Del Alcazar, , , , , Michael U.J. Oliphant, Shanshan Xie, Ethan D. Krop, Bethlehem Lulseged, Katherine C. Murphy, et al.
Cancer Immunology Research; https://doi.org/10.1158/2326-6066.cir-21-0804

Abstract:
Animal models are critical for the preclinical validation of cancer immunotherapies. Unfortunately, mouse breast cancer models do not faithfully reproduce the molecular subtypes and immune environment of the human disease. In particular, there are no good murine models of estrogen receptor–positive (ER+) breast cancer, the predominant subtype in patients. Here, we show that Nitroso-N-methylurea–induced mammary tumors in outbred Sprague-Dawley rats recapitulate the heterogeneity for mutational profiles, ER expression, and immune evasive mechanisms observed in human breast cancer. We demonstrate the utility of this model for preclinical studies by dissecting mechanisms of response to immunotherapy using combination TGFBR inhibition and PD-L1 blockade. Short-term treatment of early-stage tumors induced durable responses. Gene expression profiling and spatial mapping classified tumors as inflammatory and noninflammatory, and identified IFNγ, T-cell receptor (TCR), and B-cell receptor (BCR) signaling, CD74/MHC II, and epithelium-interacting CD8+ T cells as markers of response, whereas the complement system, M2 macrophage phenotype, and translation in mitochondria were associated with resistance. We found that the expression of CD74 correlated with leukocyte fraction and TCR diversity in human breast cancer. We identified a subset of rat ER+ tumors marked by expression of antigen-processing genes that had an active immune environment and responded to treatment. A gene signature characteristic of these tumors predicted disease-free survival in patients with ER+ Luminal A breast cancer and overall survival in patients with metastatic breast cancer receiving anti–PD-L1 therapy. We demonstrate the usefulness of this preclinical model for immunotherapy and suggest examination to expand immunotherapy to a subset of patients with ER+ disease. See related Spotlight by Roussos Torres, p. 672
, Emma J. West, Jonathan Carmichael, , Samantha Turnbull, Bethany Kuszlewicz, , Adam Peckham-Cooper, Emma Tidswell, Jennifer Kingston, et al.
Cancer Immunology Research; https://doi.org/10.1158/2326-6066.cir-21-0171

Abstract:
Improving the chances of curing patients with cancer who have had surgery to remove metastatic sites of disease is a priority area for cancer research. Pexa-Vec (Pexastimogene Devacirepvec; JX-594, TG6006) is a principally immunotherapeutic oncolytic virus that has reached late-phase clinical trials. We report the results of a single-center, nonrandomized biological end point study (trial registration: EudraCT number 2012-000704-15), which builds on the success of the presurgical intravenous delivery of oncolytic viruses to tumors. Nine patients with either colorectal cancer liver metastases or metastatic melanoma were treated with a single intravenous infusion of Pexa-Vec ahead of planned surgical resection of the metastases. Grade 3 and 4 Pexa-Vec–associated side effects were lymphopaenia and neutropaenia. Pexa-Vec was peripherally carried in plasma and was not associated with peripheral blood mononuclear cells. Upon surgical resection, Pexa-Vec was found in the majority of analyzed tumors. Pexa-Vec therapy associated with IFNα secretion, chemokine induction, and resulted in transient innate and long-lived adaptive anticancer immunity. In the 2 patients with significant and complete tumor necrosis, a reduction in the peripheral T-cell receptor diversity was observed at the time of surgery. These results support the development of presurgical oncolytic vaccinia virus-based therapies to stimulate anticancer immunity and increase the chances to cure patients with cancer.
Pierre-Florent Petit, Raphaële Bombart, Pierre-Hubert Desimpel, Stefan Naulaerts, Laurie Thouvenel, , ,
Cancer Immunology Research; https://doi.org/10.1158/2326-6066.cir-21-0801

Abstract:
Monoclonal antibodies (mAbs) blocking immune checkpoints such as programmed death ligand 1 (PD-L1) have yielded strong clinical benefits in many cancer types. Still, the current limitations are the lack of clinical response in a majority of patients and the development of immune-related adverse events in some. As an alternative to PD-L1–specific antibody injection, we have developed an approach based on the engineering of tumor-targeting T cells to deliver intratumorally an anti–PD-L1 nanobody. In the MC38-OVA model, our strategy enhanced tumor control as compared with injection of PD-L1–specific antibody combined with adoptive transfer of tumor-targeting T cells. As a possible explanation for this, we demonstrated that PD-L1–specific antibody massively occupied PD-L1 in the periphery but failed to penetrate to PD-L1–expressing cells at the tumor site. In sharp contrast, locally delivered anti–PD-L1 nanobody improved PD-L1 blocking at the tumor site while avoiding systemic exposure. Our approach appears promising to overcome the limitations of immunotherapy based on PD-L1–specific antibodies.
Ran You, Jordan Artichoker, Arja Ray, Hugo Gonzalez Velozo, Dan A. Rock, Kip P. Conner,
Cancer Immunology Research; https://doi.org/10.1158/2326-6066.cir-21-0594

Abstract:
Bispecific T-cell engager (BiTE) molecules are biologic T cell–directing immunotherapies. Blinatumomab is approved for treatment of B-cell malignancies, but BiTE molecule development in solid tumors has been more challenging. Here, we employed intravital imaging to characterize exposure and pharmacodynamic response of an anti-muCD3/anti-huEGFRvIII mouse surrogate BiTE molecule in EGFR variant III (EGFRvIII)-positive breast tumors implanted within immunocompetent mice. Our study revealed heterogeneous temporal and spatial dynamics of BiTE molecule extravasation into solid tumors, highlighting physical barriers to BiTE molecule function. We also discovered that high, homogeneous EGFRvIII expression on cancer cells was necessary for a BiTE molecule to efficiently clear tumors. In addition, we found that resident tumor-infiltrating lymphocytes (TIL) were sufficient for optimal tumor killing only at high BiTE molecule dosage, whereas inclusion of peripheral T-cell recruitment was synergistic at moderate to low dosages. We report that deletion of stimulatory conventional type I DCs (cDC1) diminished BiTE molecule–induced T-cell activation and tumor clearance, suggesting that in situ antigen-presenting cell (APC) engagements modulate the extent of BiTE molecule efficacy. In summary, our work identified multiple requirements for optimal BiTE molecule efficacy in solid tumors, providing insights that could be harnessed for solid cancer immunotherapy development.
, , Renee B. Chang, , Devora Delman, Joey H. Li, , Logan Y. Zhang, Jiasi Vicky Zhang, , et al.
Cancer Immunology Research; https://doi.org/10.1158/2326-6066.cir-21-1050

Abstract:
Glioblastoma (GBM) is an immunologically "cold" tumor characterized by poor responsiveness to immunotherapy. Standard-of-care for GBM is surgical resection followed by chemoradiotherapy and maintenance chemotherapy. However, tumor recurrence is the norm, and recurring tumors are found frequently to have acquired molecular changes (e.g. mutations) that may influence their immunobiology. Here, we compared the immune contexture of de novo and recurrent GBM (rGBM) using high-dimensional cytometry and multiplex immunohistochemistry. Although myeloid and T cells were similarly abundant in de novo and rGBM, their spatial organization within tumors differed and was linked to outcomes. In rGBM, T cells were enriched and activated in perivascular regions and clustered with activated macrophages and fewer regulatory T cells. Moreover, higher expression of phosphorylated STAT1 by T cells in these regions at recurrence was associated with a favorable prognosis. Together, our data identify differences in the immunobiology of de novo and rGBM and identify perivascular T cells as potential therapeutic targets.
Cancer Immunology Research, Volume 10, pp 543-543; https://doi.org/10.1158/2326-6066.cir-22-0148

Abstract:
Three types of cytotoxic effector cells can kill tumor cells: innate natural killer (NK) cells, CD8+ CTL, and γδ T cells. In this issue, Walwyn-Brown and colleagues report new insights into the interplay between these three cell types that are integral to antitumor immunity, finding that γδ T cells can specifically suppress NK cells but not CD8+ CTLs. These results are relevant in view of the so far limited efficacy of γδ T-cell immunotherapy. See related article by Walwyn-Brown et al., (3).
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