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

Kemnade, Jan O.; Elhalawani, Hesham; Castro, Patricia; Yu, Jiang; Lai, Syeling; Ittmann, Michael; Mohamed, A.S.R.; Lai, Stephen Y.; Fuller, Clifton D.; Sikora, Andrew G.; Sandulache, Vlad C.

doi:10.1038/s41598-019-57111-5

Cited by 18 publications

(26 citation statements)

References 41 publications

(47 reference statements)

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“…Our results are consistent with a recent report demonstrating decreased CD8+ IHC staining in tobacco-exposed primary HPV(+) OPSCC tumors. 13 Our investigation elucidates this phenomenon in much greater biologic detail by using a readout with multiple mRNA hybridization probes, validating in IHC, and controlling for mutational burden using our WES data. Multiple groups have described a similar inverse relationship between tobacco exposure and immune infiltration in HPV(-) HSNCC.…”

Section: Discussionmentioning

confidence: 75%

“…This hypothesis is supported by a recent report demonstrating lower CD8+ immunohistochemical (IHC) staining in tobacco-exposed HPV(+) tumors. 13 No prior investigation has systematically evaluated the molecular features associated with tobacco, comparing both its mutational and tumor immune effects. Using a multi-omics approach, we tested both of these hypotheses in a cohort of HPV(+) OPSCC patients.…”

Section: Introductionmentioning

confidence: 99%

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Comparative Multiomic Analysis Reveals Low T Cell Infiltration as the Primary Feature of Tobacco Use in HPV(+) Oropharyngeal Cancer

Wahle

Zolkind²,

Ramirez³

et al. 2021

Preprint

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Purpose: Tobacco use is an independent adverse prognostic feature in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Despite this, the biologic features associated with tobacco use have not been systematically investigated in this population. We sought to characterize the genomic and immunologic features of HPV(+) OPSCC associated with tobacco use and adverse oncologic outcomes. Experimental Design: Whole exome sequencing of 47 primary HPV(+) OPSCC tumors was performed to investigate mutational differences associated with tobacco exposure. To characterize the tumor immune microenvironment (TIME), targeted mRNA hybridization was performed and immunohistochemical (IHC) staining was used to validate these findings. Results: Low expression of transcripts in a T cell-inflamed gene expression profile (TGEP) was associated with tobacco use at the time of diagnosis and lower overall and disease-free survival. Tobacco use was associated with an increased proportion of T>C substitutions and a lower proportion of mutational signatures typically observed in HPV(+) OPSCC tumors, but was not associated with increases in mutational burden or the rate of recurrent oncogenic mutations. Conclusions: In HPV(+) OPSCC, low T cell infiltration of primary tumors is associated with current tobacco use and worse oncologic outcomes. Rather than an increased mutational burden, tobacco's primary and clinically relevant association is immunosuppression of the primary TIME. An objective clinical assay like the TGEP, which quantifies immune infiltration of the primary TIME, may have value for HPV(+) OPSCC risk stratification in future clinical trials.

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Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Comparative Multiomic Analysis Reveals Low T Cell Infiltration as the Primary Feature of Tobacco Use in HPV(+) Oropharyngeal Cancer

Wahle

Zolkind²,

Ramirez³

et al. 2021

Preprint

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“…Smoking is also a likely driver of poor outcomes, particularly in the Veteran population with high rates of tobacco use. Smoking worsens prognosis in HPV‐positive OPSCC, increasing the risk of death by 1% for every one pack‐year of smoking 30‐32 . However, to date, few studies have considered the interaction between HIV and HPV in OPSCC, and one previous study of OPSCC among PWLH found no difference in survival by HPV status, 33 This discordance justifies additional examination of the interaction between HPV and HIV in OPSCC specifically.…”

Section: Discussionmentioning

confidence: 99%

Incidence and survival for oropharynx and non‐oropharynx head and neck cancers among veterans living with HIV

et al. 2020

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“…Analysis of TILs was performed on all pretreatment tumor specimens as previously described using conventional immunohistochemistry coupled to quantitative imaging. 30…”

Section: Clinical Datasetmentioning

confidence: 99%

“…We previously reported on TILs as a predictor of oncologic outcomes in Veterans with HNSCC limited to the oropharynx site. 30 In the current study, we performed a secondary analysis of this dataset using clinically annotated data regarding the presence of diabetes mellitus (DM) at the time of cancer diagnosis and metformin utilization at the time of diagnosis and during treatment delivery. Of 143 patients, 21 patients carried a diagnosis of DM; among these, 11 patients were taking metformin at time of diagnosis and during treatment and 10 were utilizing other means of glycemic control.…”

Section: Chronic Metformin Treated Tumors Are Characterized By An Increased Immune Infiltratementioning

confidence: 99%

Metformin generates profound alterations in systemic and tumor immunity with associated antitumor effects

Veeramachaneni

Newton

et al. 2021

J Immunother Cancer

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BackgroundMetformin is a commonly used antidiabetic medication which has demonstrated promise as an anticancer agent alone and in combination with conventional treatment regimens. There is increasing evidence that metformin can also generate immunomodulatory effects in solid tumors and is currently being investigated as an adjunct to immune checkpoint inhibitors (ICIs). We hypothesized that metformin would generate a shift in immunity unfavorable to tumor growth and tested this hypothesis in a preclinical model of head and neck cancer.MethodsUsing a syngeneic mouse model of human papillomavirus-associated head and neck cancer (mEER/MTEC), we tested the impact of metformin on systemic and local immunity and tumor growth velocity. We compared the effects of acute and chronic treatment regimens on immunocyte presence and activation using a combination of flow cytometry and targeted transcriptomic analysis.ResultsAcute metformin exposure generated measurable shifts in systemic myeloid and T-cell populations in non-tumor-bearing mice and decreased myeloid derived suppressor cell (MDSC) levels in tumor draining lymph nodes of tumor-bearing mice. Although metformin decreased regulatory T-cell (T-reg) and MDSC levels and increased CD8+ levels in murine tumors when combined with ICIs, acute metformin exposure was insufficient to generate substantial antitumor activity. Conversely, long-term metformin treatment significantly reduced tumor growth velocity, increased the CD8+/T-reg ratio, increased tumor infiltrating lymphocyte levels and upregulated component genes of the previously validated T-cell inflamed expression profile.ConclusionsMetformin generates complex systemic and local immune effects which vary as a function of treatment duration. Combinatorial strategies with ICIs must take into account both the complexity and variability of these effects in order to generate maximal antitumor activity in future clinical trials.

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

Cited by 18 publications

References 41 publications

Comparative Multiomic Analysis Reveals Low T Cell Infiltration as the Primary Feature of Tobacco Use in HPV(+) Oropharyngeal Cancer

Comparative Multiomic Analysis Reveals Low T Cell Infiltration as the Primary Feature of Tobacco Use in HPV(+) Oropharyngeal Cancer

Incidence and survival for oropharynx and non‐oropharynx head and neck cancers among veterans living with HIV

Metformin generates profound alterations in systemic and tumor immunity with associated antitumor effects

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