Germline HLA-B evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer

Abstract Background The human leukocyte antigen class I (HLA-I) genotype has been linked with differential immune responses to infectious disease and cancer. However, the clinical relevance of germline HLA-mediated immunity in gastrointestinal (GI) cancer remains elusive. Methods This study retrospectively analyzed the genomic profiling data from 84 metastatic GI cancer patients treated with immune checkpoint blockade (ICB) recruited from Peking University Cancer Hospital (PUCH). A publicly available dataset from the Memorial Sloan Kettering (MSK) Cancer Center (MSK GI cohort) was employed as the validation cohort. For the PUCH cohort, we performed HLA genotyping by whole exome sequencing (WES) analysis on the peripheral blood samples from all patients. Tumor tissues from 76 patients were subjected to WES analysis and immune oncology-related RNA profiling. We studied the associations of two parameters of germline HLA as heterozygosity and evolutionary divergence (HED, a quantifiable measure of HLA-I evolution) with the clinical outcomes of patients in both cohorts. Results Our data showed that neither HLA heterozygosity nor HED at the HLA-A/HLA-C locus correlated with the overall survival (OS) in the PUCH cohort. Interestingly, in both the PUCH and MSK GI cohorts, patients with high HLA-B HED showed a better OS compared with low HLA-B HED subgroup. Of note, a combinatorial biomarker of HLA-B HED and tumor mutational burden (TMB) may better stratify potential responders. Furthermore, patients with high HLA-B HED were characterized with a decreased prevalence of multiple driver gene mutations and an immune-inflamed phenotype. Conclusions Our results unveil how HLA-B evolutionary divergence influences the ICB response in patients with GI cancers, supporting its potential utility as a combinatorial biomarker together with TMB for patient stratification in the future.

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Germline HLA-B evolutionary divergence to influence efficacy of immune checkpoint blockade therapy in gastrointestinal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16101 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16101-e16101

Author(s):

Zhihao Lu ◽

Lin Shen ◽

Henghui Zhang ◽

Huan Chen ◽

Xi Jiao ◽

...

Keyword(s):

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Sequence Divergence ◽

Immune Checkpoint Blockade ◽

Cancer Center ◽

Evolutionary Divergence ◽

Immune Microenvironment ◽

Peripheral Blood Mononuclear ◽

Rna Profiling ◽

Gi Cancer

e16101 Background: To date, although a number of biomarker-related investigations have focused on the intrinsic properties of tumor cells and immune microenvironment, how germline genetics influences efficacy of immune checkpoint inhibitors (ICIs) immunotherapy in gastrointestinal (GI) cancer is scarcely understood. Methods: Our investigation enrolled 94 metastatic GI cancer patients treated with ICIs recruited from Peking University Cancer Hospital (PUCH) between August 1, 2015, and May 24, 2019. A publicly available dataset from the Memorial Sloan Kettering (MSK) Cancer Center (MSK GI cohort) was used for validation. For the PUCH cohort, we performed HLA genotyping by whole exome sequencing (WES) analysis on the peripheral blood mononuclear cell (PBMC) from all 94 patients. Tumor tissues from 86 patients were subjected to WES analysis and immune oncology-related RNA profiling. Results: We assessed the clinic relevance of germline HLA heterozygosity and evolutionary divergence (HED, a quantifiable measure of HLA-I evolution) to immunotherapy in patients with advanced GI cancers from the PUCH cohort. Our data showed that neither HLA heterozygosity nor mean HED correlated with the overall survival (OS) in the PUCH cohort. However, patients with high HLA-B HED showed a better OS and durable clinic benefit (DCB) rate compared with the lower subgroup (p < 0.05 for all comparison). The prognostic value of HLA-B HED was consistently validated in the MSK GI cohort (N = 84). Notably, a combinatorial biomarker based on HLA-B HED and tumor mutation burden (TMB) could better stratify potential responders (86 patients with tumor samples). Survival analysis performed on the PUCH and MSK GI cancer datasets further demonstrated the potential joint utility of HLA-B HED and TMB for prognosis stratification. Moreover, HLA-B HED high subgroup was characterized with a lower prevalence of TP53 mutation and enrichment of multiple immune related pathways, indicating an immune-inflamed phenotype of this subgroup. Conclusions: Taken together, our data create an intriguing argument for the germline HLA-B sequence divergence and TMB as complementary biomarkers in guiding patient selection for GI cancer immunotherapy. Further investigation revealed a potential HLA-B restricted mutational pattern of TP53, and can be indicative of tumor immune microenvironment in GI cancer.

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Tumor copy-number alterations predict response to immune-checkpoint-blockade in gastrointestinal cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000374 ◽

2020 ◽

Vol 8 (2) ◽

pp. e000374 ◽

Cited By ~ 1

Author(s):

Zhihao Lu ◽

Huan Chen ◽

Shuang Li ◽

Jifang Gong ◽

Jian Li ◽

...

Keyword(s):

Cancer Patients ◽

Immune Checkpoint ◽

Clinical Benefit ◽

Copy Number ◽

Validation Cohort ◽

Predictive Biomarkers ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Copy Number Alterations ◽

Gi Cancer

BackgroundDespite the great achievements made in immune-checkpoint-blockade (ICB) in cancer therapy, there are no effective predictive biomarkers in gastrointestinal (GI) cancer.MethodsThis study included 93 metastatic GI patients treated with ICBs. The first cohort comprising 73 GI cancer patients were randomly assigned into discovery (n=44) and validation (n=29) cohorts. Comprehensive genomic profiling was performed on all samples to determine tumor mutational burden (TMB) and copy-number alterations (CNAs). A subset of samples was collected for RNA immune oncology (IO) panel sequencing, microsatellite instability (MSI)/mismatch repair and program death ligand 1 (PD-L1) expression evaluation. In addition, 20 gastric cancer (GC) patients were recruited as the second validation cohort.ResultsIn the first cohort of 73 GI cancer patients, a lower burden of CNA was observed in patients with durable clinical benefit (DCB). In both the discovery (n=44) and validation (n=29) subsets, lower burden of CNA was associated with an improved clinical benefit and better overall survival (OS). Efficacy also correlated with a higher TMB. Of note, a combinatorial biomarker of TMB and CNA may better stratify DCB patients from ICB treatment, which was further confirmed in the second validation cohort of 20 GC patients. Finally, patients with lower burden of CNA revealed increased immune signatures in our cohort and The Cancer Genome Atlas data sets as well.ConclusionsOur results suggest that the burden of CNA may have superior predictive value compared with other signatures, including PD-L1, MSI and TMB. The joint biomarker of CNA burden and TMB may better stratify DCB patients, thereby providing a rational choice for GI patients treated with ICBs.

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Abstract 281: Evaluation of circular RNA profiling in metastatic melanoma patients treated with immune checkpoint blockade

10.1158/1538-7445.am2020-281 ◽

2020 ◽

Author(s):

Juan Luis Onieva ◽

Javier Oliver ◽

Aurora Laborda-Illanes ◽

Maria Rosario Chica-Parrado ◽

Alicia Garrido-Aranda ◽

...

Keyword(s):

Metastatic Melanoma ◽

Immune Checkpoint ◽

Circular Rna ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Rna Profiling ◽

Melanoma Patients

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Mutations Associated with No Durable Clinical Benefit to Immune Checkpoint Blockade in Non-S-Cell Lung Cancer

Cancers ◽

10.3390/cancers13061397 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1397

Author(s):

Guangsheng Zhu ◽

Dian Ren ◽

Xi Lei ◽

Ruifeng Shi ◽

Shuai Zhu ◽

...

Keyword(s):

Lung Cancer ◽

Cell Lung Cancer ◽

Immune Checkpoint ◽

Clinical Benefit ◽

Gene Mutations ◽

Predictive Biomarker ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Related Gene ◽

Nsclc Patients

(1) Background: The immune checkpoint blockade (ICB) has shown promising efficacy in non-small-cell lung cancer (NSCLC) patients with significant clinical benefits and durable responses, but the overall response rate to ICBs is only 20%. The lack of responsiveness to ICBs is currently a central problem in cancer immunotherapy. (2) Methods: Four public cohorts comprising 2986 patients with NSCLC were included in the study. We screened 158 patients with NSCLC with no durable clinical benefit (NDB) to ICBs in the Rizvi cohort and identified NDB-related gene mutations in these patients using univariate and multivariate Cox regression analyses. Programmed death-ligand 1 (PD-L1) expression, tumor mutation burden (TMB), neoantigen load, tumor-infiltrating lymphocytes, and immune-related gene expression were analyzed for identifying gene mutations. A comprehensive predictive classifier model was also built to evaluate the efficacy of ICB therapy. (3) Results: Mutations in FAT1 and KEAP1 were found to correlate with NDB in patients with NSCLC to ICBs; however, the analysis suggested that only mutation in FAT1 was valuable in predicting the efficacy of ICB therapy, and that mutation in KEAP1 acted as a prognostic but not a predictive biomarker for NSCLC. Mutations in FAT1 were associated with a higher TMB and lower multiple lymphocyte infiltration, including CD8 (T-Cell Surface Glycoprotein CD8)+ T cells. We established a prognostic model according to PD-L1 expression, TMB, smoking status, treatment regimen, treatment type, and FAT1 mutation, which indicated good accuracy by receiver operating characteristic (ROC) analysis (area under the curve (AUC) for 6-months survival: 0.763; AUC for 12-months survival: 0.871). (4) Conclusions: Mutation in FAT1 may be a predictive biomarker in patients with NSCLC who exhibit NDB to ICBs. We proposed an FAT1 mutation-based model for screening more suitable NSCLC patients to receive ICBs that may contribute to individualized immunotherapy.

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DNA damage response (DDR) gene mutations (mut), mut load, and sensitivity to chemotherapy plus immune checkpoint blockade in urothelial cancer (UC).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.300 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 300-300 ◽

Cited By ~ 4

Author(s):

Matt D. Galsky ◽

Andrew V. Uzilov ◽

Russell Bailey McBride ◽

Huan Wang ◽

Vaibhav G. Patel ◽

...

Keyword(s):

Exome Sequencing ◽

Immune Checkpoint ◽

Predictive Value ◽

Objective Response ◽

Gene Mutations ◽

Progression Free Survival ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Response To Treatment ◽

Cd8 Cells

300 Background: Somatic mut in DDR genes have been associated with increased sensitivity to cisplatin in UC. Higher mut load has correlated with response to immune checkpoint blockade. We hypothesized that DDR mut result in higher mut load and DDR mut UC may be particularly sensitive to both chemotherapy and immune checkpoint blockade. Methods: Three cohorts were utilized: (1) TCGA UC cohort (n = 389), (2) Mount Sinai (MS) cohort (n = 67) of UC (cystectomy) specimens subjected to targeted exome sequencing for 341 genes (MSK-IMPACT), and (3) Phase 2 trial of gemcitabine, cisplatin, plus ipilimumab (GCI) in metastatic UC from which 28/36 enrolled patients (pts) had specimens suitable for whole exome sequencing. DDR mut were defined as somatic alterations in one of 52 genes. Deleterious (del) mut were defined as nonsense, frameshift, splice site, or hotspot point mut. Results: The mut load using all genes in the TCGA cohort, and restricted to the 341 IMPACT genes, were highly correlated (rs= 0.81, p < 0.001). Associations between del DDR mut and mut load are shown (Table). In the MS cohort, CD8+cells/mm2 by IHC were higher in tumors with del DDR mut versus no DDR mut (p = 0.04). In the GCI cohort, the sensitivity, specificity, positive predictive value, and negative predictive value of a del DDR mut for objective response to treatment was 40.9% (95% CI 20.7-63.7%), 86.7% (95% CI 42.1-99.4%), 90% (55.5-99.8%), and 31.6% (95% CI 12.6-56.6%), respectively. Median progression-free survival in the GCI cohort was 308 days (95% CI 270-NR) in del DDR mut and 196 days (95% CI 185-372) in others (p = 0.24). Notably, 2/9 pts with del DDR mutations, and with the highest mut loads, achieved complete responses after GCI and are alive without evidence of disease at 2.1+ and 1.8+ years. Conclusions: DDR mut are associated with higher mut load in UC, a high likelihood of response to GCI, and may identify a subset of pts achieving durable disease control. GC plus PD-1/PD-L1 blockade should be explored in DDR mut UC. Clinical trial information: NCT01524991. [Table: see text]

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Success and failure of additional immune modulators in steroid-refractory/resistant pneumonitis related to immune checkpoint blockade

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001884 ◽

2021 ◽

Vol 9 (2) ◽

pp. e001884

Author(s):

Jason Beattie ◽

Hira Rizvi ◽

Paige Fuentes ◽

Jia Luo ◽

Adam Schoenfeld ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Modulation ◽

Treatment Strategies ◽

High Volume ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Cancer Center ◽

Necrosis Factor Alpha ◽

Immune Modulators ◽

Steroid Refractory

BackgroundPneumonitis related to immune checkpoint blockade is uncommon but can be severe, fatal or chronic. Steroids are first-line treatment, however, some patients are refractory or become resistant to steroids. Like many immune-related adverse events, little is known regarding the outcomes and optimal management of patients in whom steroids are ineffective.MethodsWe performed a single-center retrospective cohort study at a high-volume tertiary cancer center to evaluate the clinical course, management strategies and outcomes of patients treated for immune checkpoint pneumonitis with immune modulatory medications in addition to systemic steroids. Pharmacy records were queried for patients treated with both immune checkpoint blockade and receipt of additional immune modulators. Records were then manually reviewed to identify patients who received the additional immune modulators for immune checkpoint pneumonitis.ResultsFrom 2013 to 2020, we identified 26 patients treated for immune checkpoint pneumonitis with additional immune modulators in addition to steroids. Twelve patients (46%) were steroid-refractory and 14 (54%) were steroid-resistant. Pneumonitis severity included grade 2 (42%) or grade 3–4 (58%). Additional immune modulation consisted of tumor necrosis factor-alpha inhibitor (77%) and/or mycophenolate (23%). Durable improvement in pneumonitis following initiation of additional immune modulators occurred in 10 patients (38%), including three patients (12%) in whom pneumonitis resolved and all immunosuppressants ceased. The rate of 90-day all-cause mortality/hospice referral was 50%. At last follow-up, mortality attributable to pneumonitis was 23%. In addition to mortality from pneumonitis and cancer, 3 patients (12%) died due to infections possibly associated with immunosuppression.ConclusionsSteroid-refractory or -resistant immune checkpoint pneumonitis is uncommon but associated with significant morbidity and mortality. Additional immunomodulators can yield durable improvement, attained in over one third of patients. An improved understanding of the underlying biology of immune-related pneumonitis will be crucial to guide more precise and effective treatment strategies in the future.

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Expression of human leukocyte antigen-a and b2-microglobulin in prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e16550 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e16550-e16550

Author(s):

Ying-Chun Shen ◽

Yung-Ming Jeng ◽

Jhe-Cyuang Kuo ◽

Yu-Chieh Tsai ◽

Chung-Hsin Chen ◽

...

Keyword(s):

Prostate Cancer ◽

Human Leukocyte Antigen ◽

Tumor Cells ◽

Immune Checkpoint ◽

Human Leukocyte ◽

Immune Checkpoint Blockade ◽

Significant Loss ◽

Checkpoint Blockade ◽

Leukocyte Antigen ◽

Antigen A

e16550 Background: Prostate cancer (PC) is generally resistant to current immune checkpoint blockade. Reduced expression of human leukocyte antigen-A (HLA-A) and b2-microglobulin (B2M) of cancer cells can cause deficit immune recognition and attack by cytotoxic T cells, and may be the major mechanism of intrinsic resistance to immune checkpoint blockade in PC patients. Methods: Formalin-fixed paraffin-embedded tissue of human localized or metastatic PC was used for evaluation of expression of HLA-A and B2M by Immunohistochemical staining. The expression was scored as: 0, no tumor cells stained; 1+, < 10% of tumor cells stained; 2+, 10-50% of tumor cells stained; and 3+, > 50% of tumor cells stained. Differences in HLA-A or B2M expression among groups were assessed by Chi-Square or Fisher’s exact test. Results: A total of 134 PC specimens [69 localized PC (LPC), 32 metastatic castration-naïve PC (mCNPC), and 33 metastatic castration-resistant PC (mCRPC)] from 115 patients were assessed. Significant loss (0 or 1+) of HLA-A was found in 56 (81.2%) LPCs, 30 (93.8 %) mCNPCs and 29 (87.9%) mCRPCs; while significant loss of B2M was found in 22 (32.6%) LPC, 11 (34.4%) mCNPCs, and 17 (51.2%) mCRPCs. In localized PCs, the expression of HLA-A or B2M was similar between high-grade prostate intraepithelial neoplasia foci and corresponding malignant counterpart, and did not significantly correlate to biochemical failure. In 14 patients with paired CN and CR PC specimens, significant loss of HLA-A was found in all tumors. B2M expression varied between CN and CR PCs, and progressive loss of B2M was found in 7 (50%) patients. Among 3 patients receiving immune checkpoint blockade, 1 patient with intact expression of HLA-A and B2M in pre-treatment tumor specimen achieved partial response; whereas the others with reduced expression of HLA-A (0) and B2M (1+) did not. Conclusions: Reduced expression of HLA-A or B2M is an early event in prostate carcinogenesis.

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Burden of copy number alterations predicts outcomes in immune checkpoint blockade treated gastrointestinal cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14068 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14068-e14068

Author(s):

Zhihao Lu ◽

Huan Chen ◽

Shuang Li ◽

Xi Jiao ◽

Lihong Wu ◽

...

Keyword(s):

Immune Checkpoint ◽

Copy Number ◽

Objective Response ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Copy Number Alterations ◽

Sequencing Platform ◽

Gi Cancer ◽

Ffpe Tumor ◽

Gi Cancers

e14068 Background: Despite the great achievements made in immune checkpoint blockade (ICB) in cancer therapy, how to identify patients who may benefit from ICB still remains one of the central questions, especially in gastrointestinal (GI) cancer. Methods: To address this, we analyzed FFPE tumor specimens from 73 patients with metastatic GI cancers who were treated with ICB. All patients were randomly assigned into discovery (60%) and validation (40%) cohorts. Overall, tumor mutation burden (TMB) and copy number alterations (CNAs) were determined by using the whole-exome sequencing platform. FFPE samples of 65 patients were analyzed via a multiplex RNA immune oncology sequencing panel. Results: Here we show that lower burden of copy number alteration (CNA) was observed in responders to immunotherapy in both discovery and validation cohorts. More importantly, lower burden of CNA in GI cancers were associated with improved objective response, clinical benefit and overall survival. Efficacy also correlated with the higher TMB. Of note, a combinatorial biomarker of TMB and burden of CNA may better stratify responders from patients received immunotherapy. In addition, patients with lower burden of CNA revealed increased IFNγ and expanded immune signatures in our GI patient cohort and TCGA cohorts as well. Conclusions: Our results suggest that burden of CNA may expand the predictive and prognostic value of genomic determinants in identifying potential responders with GI cancer to immune checkpoint blockade therapy.

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