The immune microenvironment of HPV-negative oral squamous cell carcinoma from never-smokers and never-drinkers patients suggests higher clinical benefit of IDO1 and PD1/PD-L1 blockade

Foy, Jean‐Philippe; Bertolus, Chloé; Michallet, Marie Cécile; Deneuve, Sophie; Incitti, Roberto; Bendriss‐Vermare, Nathalie; Albaret, Marie-Alexandra; Ortiz-Cuarán, Sandra; Thomas, Emilie; Colombe, Amélie; Py, C.; Gadot, Nicolas; Michot, Jean‐Marie; Fayette, Jérôme; Viari, Alain; Eynde, B. Van den; Goudot, P.; Devouassoux‐Shisheboran, Mojgan; Puisieux, Alain; Caux, Christophe; Zrounba, Philippe; Lantuéjoul, Sylvie; Saintigny, Pierre

doi:10.1093/annonc/mdx210

Cited by 77 publications

(93 citation statements)

References 31 publications

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“…It is also conceivable that short-term viral exposure induces APOBEC activation and carcinogenesis without genomic viral integration in some patients. A subgroup of HPV-negative oral squamous cell carcinoma patients in neversmokers, never-drinkers with high tumor inflammation has been described in the literature, accordingly and might correspond with our observation (Foy et al, 2017). Further research focusing on the impact of short-term viral exposure and APOBEC-activation or virusindependent mechanisms of APOBEC-activation, especially in this hard-to-treat subgroup, are of interest.…”

Section: Discussionsupporting

confidence: 87%

Distinct immune evasion in APOBEC-enriched, HPV-negative HNSCC

Messerschmidt

Obermayer

Klinghammer

et al. 2019

Preprint

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Immune checkpoint inhibition leads to response in some patients with head and neck squamous cell carcinoma (HNSCC). Robust biomarkers are lacking to date. We analyzed viral status, gene expression signatures, mutational load and mutational signatures in whole exome and RNA-sequencing data of the HNSCC TCGA dataset (N = 496) and a validation set (DKTK MASTER cohort, N = 10). Public single-cell gene expression data from 17 HPV-negative HNSCC were separately re-analyzed. Among HPV-negative HNSCC, APOBEC3-associated TCW motif mutations but not total single nucleotide variant burden were significantly associated with inflammation. APOBEC3enriched HPV-negative HNSCC showed higher T-cell inflammation and immune checkpoint expression. Mutations in immune-evasion pathways were enriched in these tumors. APOBEC3B and 3C expression was identified in tumor cells and correlated with tumor inflammation. We identified an APOBEC-enriched subgroup of HPV-negative HNSCC with a distinct immunogenic phenotype, potentially mediating response to immunotherapy.

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Section: Discussionsupporting

confidence: 87%

Distinct immune evasion in APOBEC-enriched, HPV-negative HNSCC

Messerschmidt

Obermayer

Klinghammer

et al. 2019

Preprint

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“…Biological differences in the immune microenvironment are mainly responsible for response to immunotherapy in various tumor types. For an example, increased IFNγ and PD1 pathways, higher CD8 + T cell infiltrates, with PD‐L1 and IDO‐1 overexpression was associated with a higher score of response signature to pembrolizumab in HPV‐negative oral squamous cell carcinoma . In addition, IDO‐1 overexpression has been noticed in pretreatment melanomas from responders to PD‐L1 inhibition .…”

Section: Discussionmentioning

confidence: 96%

“…24 | 1587 pathways, higher CD8 + T cell infiltrates, with PD-L1 and IDO-1 overexpression was associated with a higher score of response signature to pembrolizumab in HPV-negative oral squamous cell carcinoma. 29 In addition, IDO-1 overexpression has been noticed in pretreatment melanomas from responders to PD-L1 inhibition. 30 In this study, we evaluated for the first time the IDO-1 activity within the tumor microenvironment of primary RCC specimens and its role as a possible pretreatment biomarker for predicting response to immunotherapy.…”

Section: Ido-1 Expression Was Totally Absent In Tumor Cells and Was Onlymentioning

confidence: 99%

High IDO‐1 expression in tumor endothelial cells is associated with response to immunotherapy in metastatic renal cell carcinoma

et al. 2018

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Nivolumab belongs to the standard therapy in the second‐line setting of metastatic renal cell carcinoma (mRCC). Although deep and long‐lasting responses are seen in some patients, the majority of patients will further progress. PD‐L1 is still under critical evaluation as a predictive biomarker. Thus, more accurate biomarkers are clearly warranted. Here, we investigated for the first time the predictive role of IDO‐1, a negative immune‐regulatory molecule, on clear cell RCC tissues of 15 patients undergoing nivolumab therapy. IDO‐1 and other immune inhibitory molecules (PD‐L1, PD‐L2, FOXP3) as well as immune cell subsets (CD3, CD4 and CD8) were measured on formalin‐fixed, paraffin‐embedded sections of RCC specimens by immunohistochemistry. IDO‐1 was predominantly expressed in tumor endothelial cells, and was totally absent from tumor cells itself. IDO‐1 overexpression (>10%) could be detected more frequently in responders (100%, n = 6/6) compared to non‐responders (33.3%, n = 3/9; P = .028), resulting in a better progression‐free survival during immunotherapy (IDO‐1 ≤ 10% vs >10%, median: 3.5 vs not estimated (NE) months, P = .01 by log‐rank test). In addition, IDO‐1 was positively correlated with CD8+ T cell expression (r s = .691, P = .006). PD‐L1 expression on tumor cells was negative in 13 (86.7%) of 15 patients, irrespective of therapeutic response (responders vs non‐responders: 83.3% vs 88.9%). No differences were noticed in the PD‐L1 expression on tumor‐infiltrating immune cells (PD‐L1 < 1% in 66.7% of both responders and non‐responders). In contrast to PD‐L1, these results suggest that IDO‐1 may be a more promising predictive biomarker for response to immune‐based cancer therapy in mRCC.

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“…These effects are broad based and are not completely consistent across solid tumor types as shown in a recent TCGA analysis of head and neck and lung tumors 13 . A recent analysis of several datasets from oral cavity SCC (OCSCC) demonstrated that changes in the tumor immune microenvironment were the primary effect noted secondary to variable tobacco exposure 43 . The current analysis extends these previous datasets in two overlapping ways.…”

Section: Discussionmentioning

confidence: 99%

CD8 infiltration is associated with disease control and tobacco exposure in intermediate-risk oropharyngeal cancer

Kemnade

Elhalawani

Castro

et al. 2020

Sci Rep

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Oropharyngeal squamous cell carcinoma (OPSCC) incidence is increasing at a nearly epidemic rate, largely driven by the human papillomavirus (HPV). Despite the generally favorable clinical outcomes of patients with HPV driven (HPV+) OPSCC, a significant subset of HPV tumors associated with tobacco exposure have diminished treatment response and worse survival. The tumor immune microenvironment (TIME) has been shown to be a critical driver of treatment response and oncologic outcomes in OPSCC generally and HPV+ OPSCC more specifically. However, the impact of tobacco exposure on the TIME in OPSCC patients remains unclear. We analyzed the relationship between TIME, tobacco exposure and clinical outcomes in OPSCC patients (n = 143) with extensive tobacco exposure (median pack-years = 40). P16 overexpression, a surrogate marker of HPV association, was a strong predictor of relapse-free (RFS) and overall survival (OS) (p < 0.001, p < 0.001 respectively) regardless of tobacco exposure and associated strongly with differential infiltration of the tumor by both CD3 and CD8 lymphocytes measured via immunohistochemistry (p < 001, p < 0.001 respectively). CD3 and CD8 infiltration was a strong predictor of RFS and OS and associated strongly with disease stage (AJCC 8 th Edition Staging Manual). Tobacco exposure correlated significantly (p < 0.001) with decreased CD8 infiltration in p16+ OPSCC tumors. Our findings demonstrate that the HPV+ OPSCC clinical outcomes are strongly correlated with the TIME, which is potentially modulated by tobacco exposure. Immunomodulatory strategies targeting this disease in smokers must take into consideration the potential modifying effects of tobacco exposure on treatment effectiveness and clinical outcomes.

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The immune microenvironment of HPV-negative oral squamous cell carcinoma from never-smokers and never-drinkers patients suggests higher clinical benefit of IDO1 and PD1/PD-L1 blockade

Cited by 77 publications

References 31 publications

Distinct immune evasion in APOBEC-enriched, HPV-negative HNSCC

Distinct immune evasion in APOBEC-enriched, HPV-negative HNSCC

High IDO‐1 expression in tumor endothelial cells is associated with response to immunotherapy in metastatic renal cell carcinoma

CD8 infiltration is associated with disease control and tobacco exposure in intermediate-risk oropharyngeal cancer

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