Germline HLA landscape does not predict efficacy of pembrolizumab monotherapy across solid tumor types

Chhibber, Aparna; Huang, Lingkang; Zhang, Hong; Xu, Jialin; Cristescu, Rǎzvan; Liu, Xiaoqiao; Mehrotra, Devan V.; Shen, Judong; Shaw, Peter M.; Hellmann, Matthew D.; Snyder, Alexandra

doi:10.1016/j.immuni.2021.12.006

Cited by 25 publications

(21 citation statements)

References 52 publications

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“…Such pretreatment biomarkers can help inform clinical judgment and lead to better outcomes by identifying progression events sooner, limiting usage of ineffective and costly ICB regimens, and improving patient quality of life by potentially transitioning to the next line of therapy before asymptomatic progression becomes symptomatic progression. We note that biomarkers considering HLA-LOH and HLA diversity alone have produced contradictory results in predicting ICB outcomes 9,14,15,69 . Such HLA-I deficiencies are thought to limit tumor antigen presentation to CD8 + T cells but do not account for the potential role of cytotoxic CD4 + T cells.…”

Section: Discussionmentioning

confidence: 84%

“…Leiden clustering was performed using Scanpy with a resolution of 0.7 for the CD8 cells and 0.8 for the CD4 cells. Cell cycle status was assessed using the score_genes_cell_cycle function in Scanpy with the gene list from Tirosh et al 69 PAGA graphs were generated with the paga function in Scanpy with 6 neighbors and the first 20 principal components. Differential expression analysis was performed using the rank_genes_groups function in Scanpy with the Wilcoxon Rank-Sum test.…”

Section: Methodsmentioning

confidence: 99%

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Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer

et al. 2022

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The efficacy of immune checkpoint blockade (ICB) varies greatly among metastatic non-small cell lung cancer (NSCLC) patients. Loss of heterozygosity at the HLA-I locus (HLA-LOH) has been identified as an important immune escape mechanism. However, despite HLA-I disruptions in their tumor, many patients have durable ICB responses. Here we seek to identify HLA-I-independent features associated with ICB response in NSCLC. We use single-cell profiling to identify tumor-infiltrating, clonally expanded CD4+ T cells that express a canonical cytotoxic gene program and NSCLC cells with elevated HLA-II expression. We postulate cytotoxic CD4+ T cells mediate anti-tumor activity via HLA-II on tumor cells and augment HLA-I-dependent cytotoxic CD8+ T cell interactions to drive ICB response in NSCLC. We show that integrating tumor extrinsic cytotoxic gene expression with tumor mutational burden is associated with longer time to progression in a real-world cohort of 123 NSCLC patients treated with ICB regimens, including those with HLA-LOH.

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Section: Discussionmentioning

confidence: 84%

Section: Methodsmentioning

confidence: 99%

Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer

et al. 2022

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“…ICI specificity) by finding no difference in OS for non‐ICI‐treated patients. However, these findings were not replicated in another recent pan‐cancer analysis of pembrolizumab (anti‐PD1)‐treated patients; thus, its clinical use remains investigational [45].…”

Section: Germline Genetic Featuresmentioning

confidence: 99%

“…They found that greater mean HED was associated with better OS and ORR in melanoma and NSCLC patients, consistent with the ‘divergent allele advantage’ theory (whereby more diverse HLA‐I allele pairs would plausibly present more diverse cancer neoantigens). However, the relationship of HLA‐I zygosity and/or mean HED and better ICI efficacy has not been consistently found in more recent analyses for non‐melanoma cohorts [45,49–51]. Importantly, the HLA‐B44 supertype seemed to impart an opposite, negative effect in NSCLC, potentially due to NSCLC's distinct neoantigen landscape (leading to worse presentation on HLA‐B44 ) [52].…”

Section: Germline Genetic Featuresmentioning

confidence: 99%

‘Know thyself’ – host factors influencing cancer response to immune checkpoint inhibitors

Gunjur

Manrique-Rincón

Klein

et al. 2022

The Journal of Pathology

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Immune checkpoint inhibitors (ICIs) have revolutionised oncology and are now standard-of-care for the treatment of a wide variety of solid neoplasms. However, tumour responses remain unpredictable, experienced by only a minority of ICI recipients across malignancy types. Therefore, there is an urgent need for better predictive biomarkers to identify a priori the patients most likely to benefit from these therapies. Despite considerable efforts, only three such biomarkers are FDA-approved for clinical use, and all rely on the availability of tumour tissue for immunohistochemical staining or genomic assays. There is emerging evidence that host factorsfor example, genetic, metabolic, and immune factors, as well as the composition of one's gut microbiotainfluence the response of a patient's cancer to ICIs. Tantalisingly, some of these factors are modifiable, paving the way for co-therapies that may enhance the therapeutic index of these treatments. Herein, we review key host factors that are of potential biomarker value for response to ICI therapy, with a particular focus on the proposed mechanisms for these influences.

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“…In a meta-analysis of factors that influence ICI efficacy, Litchfield et al also showed that HLA divergence was a significant factor influencing ICI response in melanoma ( 64 ). If HLAs are not actually typed but are estimated by imputation using microarrays, associations may be not apparent ( 99 ). Based on more recent modeling data, it appears that HED has a somewhat weaker effect compared with TMB, treatment beforehand with chemotherapy, or neutrophil/lymphocyte ratio.…”

Section: Tumor Cell–extrinsic Determinants Of Responsementioning

confidence: 99%

Next-generation sequencing: unraveling genetic mechanisms that shape cancer immunotherapy efficacy

Halima¹,

Vuong²,

Chan³

2022

Journal of Clinical Investigation

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Immunity is governed by fundamental genetic processes. These processes shape the nature of immune cells and set the rules that dictate the myriad complex cellular interactions that power immune systems. Everything from the generation of T cell receptors and antibodies, control of epitope presentation, and recognition of pathogens by the immunoediting of cancer cells is, in large part, made possible by core genetic mechanisms and the cellular machinery that they encode. In the last decade, next-generation sequencing has been used to dissect the complexities of cancer immunity with potent effect. Sequencing of exomes and genomes has begun to reveal how the immune system recognizes “foreign” entities and distinguishes self from non-self, especially in the setting of cancer. High-throughput analyses of transcriptomes have revealed deep insights into how the tumor microenvironment affects immunotherapy efficacy. In this Review, we discuss how high-throughput sequencing has added to our understanding of how immune systems interact with cancer cells and how cancer immunotherapies work.

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Germline HLA landscape does not predict efficacy of pembrolizumab monotherapy across solid tumor types

Cited by 25 publications

References 52 publications

Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer

Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer

‘Know thyself’ – host factors influencing cancer response to immune checkpoint inhibitors

Next-generation sequencing: unraveling genetic mechanisms that shape cancer immunotherapy efficacy

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