Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA

Paulson, Kelly G.; Voillet, Valentin; McAfee, Megan S.; Hunter, Daniel; Wagener, Felecia; Perdicchio, Maurizio; Valente, William J.; Koelle, Samson; Church, Candice D.; Vandeven, Natalie; Thomas, Hannah; Nghiem, Paul; Iyer, Jayasri G.; Yee, Cassian; Kulikauskas, Rima M.; Koelle, David M.; Pierce, Robert H.; Bielas, Jason H.; Greenberg, Philip D.; Bhatia, Shailender; Gottardo, Raphaël; Nghiem, Paul; Chapuis, Aude G.

doi:10.1038/s41467-018-06300-3

Cited by 214 publications

(176 citation statements)

References 52 publications

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“…In addition to LOH, transcriptional repression of individual HLA genes can also mediate acquired resistance to TCR therapies. This was recently demonstrated in two patients who received ACT of CD8 + T cells specific for an epitope derived MCPyV . The MCPyV‐specific T cells in these patients were restricted by HLA‐B*3502 and HLA‐A*02:01, respectively.…”

Section: Therapeutic Resistance To Tcr‐based Cancer Immunotherapiesmentioning

confidence: 67%

“…Analogous to the HPV E6/E7 antigens, Merkel cell carcinoma associated with MCPyV infection constitutively expresses the viral large T‐antigen (LTAg) oncoprotein. Adoptive transfer of autologous MCPyV LTAg‐specific T cells can also induce objective responses in patients with metastatic disease . Finally, ACT of T cells specific for the EBV‐associated oncoprotein LMP1 have also successfully mediated cancer regression in patients with nasopharyngeal carcinoma .…”

Section: Clinical Experience With Tcr‐based Cancer Immunotherapiesmentioning

confidence: 99%

“…Resistance to TCR‐based immunotherapies is increasingly being recognized as a clinically significant entity . Conceptually, the mechanistic basis for TCR resistance can be subdivided into the following four categories: primary (1°) versus late/acquired and T cell‐intrinsic versus extrinsic (Figure ).…”

Section: Therapeutic Resistance To Tcr‐based Cancer Immunotherapiesmentioning

confidence: 99%

“…In the case of HPV, the E6 and E7 oncoproteins are constitutively expressed and clonally maintained within patients. 193 Two HLA-A2restricted TCRs specific for epitopes derived from the HPV-16 E6 132 and E7 123 194,195 Finally, ACT of T cells specific for the EBV-associated oncoprotein LMP1 have also successfully mediated cancer regression in patients with nasopharyngeal carcinoma. 196 In each of these examples, no off-target/ off-tumor toxicities were observed.…”

Section: Virus-derived Oncoproteinsmentioning

confidence: 99%

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T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

Chandran

Klebanoff

2019

Immunological Reviews

198

158

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Adoptive cell transfer (ACT) using chimeric antigen receptor (CAR)‐modified T cells can induce durable remissions in patients with refractory B‐lymphoid cancers. By contrast, results applying CAR‐modified T cells to solid malignancies have been comparatively modest. Alternative strategies to redirect T cell specificity and cytolytic function are therefore necessary if ACT is to serve a greater role in human cancer treatments. T cell receptors (TCRs) are antigen recognition structures physiologically expressed by all T cells that have complementary, and in some cases superior, properties to CARs. Unlike CARs, TCRs confer recognition to epitopes derived from proteins residing within any subcellular compartment, including the membrane, cytoplasm and nucleus. This enables TCRs to detect a broad universe of targets, such as neoantigens, cancer germline antigens, and viral oncoproteins. Moreover, because TCRs have evolved to efficiently detect and amplify antigenic signals, these receptors respond to epitope densities many fold smaller than required for CAR‐signaling. Herein, we summarize recent clinical data demonstrating that TCR‐based immunotherapies can mediate regression of solid malignancies, including immune‐checkpoint inhibitor refractory cancers. These trials simultaneously highlight emerging mechanisms of TCR resistance. We conclude by discussing how TCR‐based immunotherapies can achieve broader dissemination through innovations in cell manufacturing and non‐viral genome integration techniques.

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Section: Therapeutic Resistance To Tcr‐based Cancer Immunotherapiesmentioning

confidence: 67%

Section: Clinical Experience With Tcr‐based Cancer Immunotherapiesmentioning

confidence: 99%

Section: Therapeutic Resistance To Tcr‐based Cancer Immunotherapiesmentioning

confidence: 99%

Section: Virus-derived Oncoproteinsmentioning

confidence: 99%

See 2 more Smart Citations

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

Chandran

Klebanoff

2019

Immunological Reviews

198

158

View full text Add to dashboard Cite

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“…Intralesional injections of IFN‐β also increase MHC I expression, CD8 T‐cell infiltration, and local tumor regression . Transcriptional suppression of MHC I may also underlie resistance to immunotherapies . Therefore, IFN may have a synergistic role with other immunotherapies.…”

Section: Discussionmentioning

confidence: 99%

Molecular and immune targets for Merkel cell carcinoma therapy and prevention

Cohen

Tsai

2019

Molecular Carcinogenesis

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Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma of the skin, for which the exact mechanisms of carcinogenesis remain unknown. Therapeutic options for this highly aggressive malignancy have historically been limited in both their initial response and response durability. Recent improvements in our understanding of MCC tumor biology have expanded therapeutic options for these patients, namely through the use of immunotherapies such as immune checkpoint inhibitors. Further elucidation of the tumor mutational landscape has identified molecular targets for therapies, which have demonstrated success in other cancer types. In this review, we discuss both current and investigational immune and molecular targets of therapy for MCC.

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Human Leukocyte Antigen Class I Antigen-Processing Machinery Upregulation by Anticancer Therapies in the Era of Checkpoint Inhibitors

et al. 2022

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IMPORTANCEAlthough typically impressive, objective responses to immune checkpoint inhibitors (ICIs) occur in only 12.5% of patients with advanced cancer. The majority of patients do not respond due to cell-intrinsic resistance mechanisms, including human leukocyte antigen (HLA) class I antigen-processing machinery (APM) defects. The APM defects, which have a negative effect on neoantigen presentation to cytotoxic T lymphocytes (CTLs), are present in the majority of malignant tumors. These defects are caused by gene variations in less than 25% of cases and by dysregulated signaling and/or epigenetic changes in most of the remaining cases, making them frequently correctable. This narrative review summarizes the growing clinical evidence that chemotherapy, targeted therapies, and, to a lesser extent, radiotherapy can correct HLA class I APM defects in cancer cells and improve responses to ICIs.OBSERVATIONS Most chemotherapeutics enhance HLA class I APM component expression and function in cancer cells, tumor CTL infiltration, and responses to ICIs in preclinical and clinical models. Despite preclinical evidence, radiotherapy does not appear to upregulate HLA class I expression in patients and does not enhance the efficacy of ICIs in clinical settings. The latter findings underscore the need to optimize the dose and schedule of radiation and timing of ICI administration to maximize their immunogenic synergy. By increasing DNA and chromatin accessibility, epigenetic agents (histone deacetylase inhibitors, DNA methyltransferase inhibitors, and EZH2 inhibitors) enhance HLA class I APM component expression and function in many cancer types, a crucial contributor to their synergy with ICIs in patients. Furthermore, epidermal growth factor receptor (EGFR) inhibitors and BRAF/mitogen-activated protein kinase kinase inhibitors are effective at upregulating HLA class I expression in EGFR-and BRAF-variant tumors, respectively; these changes may contribute to the clinical responses induced by these inhibitors in combination with ICIs.CONCLUSIONS AND RELEVANCE This narrative review summarizes evidence indicating that chemotherapy and targeted therapies are effective at enhancing HLA class I APM component expression and function in cancer cells. The resulting increased immunogenicity and recognition and elimination of cancer cells by cognate CTLs contributes to the antitumor activity of these therapies as well as to their synergy with ICIs.

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Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA

Cited by 214 publications

References 52 publications

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

Molecular and immune targets for Merkel cell carcinoma therapy and prevention

Human Leukocyte Antigen Class I Antigen-Processing Machinery Upregulation by Anticancer Therapies in the Era of Checkpoint Inhibitors

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