Functional HPV-specific PD-1+ stem-like CD8 T cells in head and neck cancer

Eberhardt, Christiane S.; Kissick, Haydn; Patel, Mihir R.; Cardenas, Maria A; Prokhnevska, Nataliya; Obeng, Rebecca C.; Nasti, Tahseen H.; Griffith, Christopher C.; Im, Se Jin; Wang, Xu; Shin, Dong M.; Carrington, Mary; Chen, Zhuo G.; Sidney, John; Sette, Alessandro; Saba, Nabil F.; Wieland, Andreas; Ahmed, Rafi

doi:10.1038/s41586-021-03862-z

Cited by 217 publications

(235 citation statements)

References 33 publications

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“…In line with our current results, a recent study noted that between nearly 10% of the infiltrating T cells present in HNSCC were such CD8-positive T cells that target HPV and express PD-1 (22). One of these cells has stem cell characteristics and can expand in large numbers to treat head and neck cancer if cancer immunotherapy is used.…”

Section: Discussionsupporting

confidence: 91%

A Tumor-Infiltration CD8+ T Cell-Based Gene Signature for Facilitating the Prognosis and Estimation of Immunization Responses in HPV+ Head and Neck Squamous Cell Cancer

Meng

Cai

et al. 2021

Front. Oncol.

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BackgroundCD8+ T cells, which play a vital role in response to adaptive immunity, are closely related to the immunization responses to kill tumor cells. Understanding the effects exerted by tumor-infiltrated CD8+ T cells in HPV+ and HPV- head and neck squamous cell carcinoma (HNSCC) patients is critical for predicting their prognosis as well as their responses towards immunization-related therapy.Materials and MethodsHNSCC single cell transcriptome was used to screen for differentially expressed genes (DEGs) based on CD8+ T cells. A gene signature associated with CD8+ T cells was built and verified with the cancer genome atlas dataset with a view to predicting the prognosis of HNSCC patients. Risk scores were calculated for HNSCC cases and categorized into either high- or low-risk cohorts. The prognosis-correlated data of the risk scores were analyzed by using Kaplan-Meier survival curves and multi-variate Cox regression plots. In addition, the possibility of using the genetic profiles to predict responses toward immunization-related therapy was explored.ResultsFrom the DEGs screened from the sequencing of single-cell RNA, a gene signature of 4 genes (ACAP1, ANKRD28, C12orf75, and M6PR) were identified. It was seen that these genes could predict overall survival in HPV+ HNSCC patients. In addition, high- and low-risk HPV+ HNSCC patients showed marked differences in their CD8+ T-cell infiltration due to immunization when clinical characteristics were taken into consideration. This correlated with their immunization therapy responses.ConclusionsOur work provides insights into explaining the restricted responses of current immunization checkpoint inhibiting substances in HPV+ HNSCC patients. A novel genetic signature to predict the prognosis and immunization-correlated therapeutic responses is presented. This will provide potential new therapeutic opportunities for HPV+ HNSCC patients.

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Section: Discussionsupporting

confidence: 91%

A Tumor-Infiltration CD8+ T Cell-Based Gene Signature for Facilitating the Prognosis and Estimation of Immunization Responses in HPV+ Head and Neck Squamous Cell Cancer

Meng

Cai

et al. 2021

Front. Oncol.

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“…for each sample and creating expression tertiles (high, intermediate, low). The distribution of C1 strata by T cell infiltration status is shown in Table 1 Fisher's exact test 4 Alteration defined a presence of mutation, copy number gain or amplification, or homozygous deletion.…”

Section: Differentially Expressed Genes (Degs) Comparing Hpv+ T Cell Infiltrated Hnscs Stratifiedmentioning

confidence: 99%

“…Features promoting anti-tumor immunity include the presence of cytotoxic tumor infiltrating lymphocytes (TILs) and antigen (e.g., viral, tumor neoantigens). [1][2][3][4] However, not all immune cell infiltrated, immunogenic tumors exhibit favorable anti-tumor immunity. The tumor microenvironment (TME) diminishes anti-tumor T cell function through recruitment of tolerogenic cell types, nutrient-depletion, and the creation of an acidic and hypoxic microenvironment.…”

Section: Introductionmentioning

confidence: 99%

“…To accomplish this, we began by selecting a cohort of human papillomavirus (HPV)-associated head and neck squamous cell carcinomas (HNSCs) characterized by CD8 T cell infiltration and virus-derived tumor-associated antigens. 4 By leveraging the immune characteristics of these tumors, we hypothesized that tumor intrinsic or extrinsic features of the TME diminish the anti-tumor immune response in some, but not all tumors, focusing on metabolic features of the TME. We leveraged genomic atlases to test our hypothesis.…”

Section: Introductionmentioning

confidence: 99%

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Interrogation of T Cell-Enriched Tumors Reveals Prognostic and Immunotherapeutic Implications of Polyamine Metabolism

Harbison

Pandey

Considine

et al. 2021

Preprint

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Background: The presence of cytotoxic tumor infiltrating lymphocytes (TILs) and antigen (e.g., viral, tumor neoantigens) enhances anti-tumor immunity. However, features including recruitment of tolerogenic cell types, nutrient-depletion, and the establishment of an acidic and hypoxic microenvironment diminish anti-tumor lymphocyte function. We sought to understand why the anti-tumor immune response fails despite a favorable immune profile. Methods: We leveraged human papillomavirus-related (HPV+) head and neck squamous cell carcinomas (HNSC) to address this question given their high degree of CD8+ T cell-infiltration and virus-derived tumor-associated antigens. We evaluated expression of 2,520 metabolic genes between HPV+ HNSCs of different prognostic phenotypes. We further tested tumor-intrinsic and -extrinsic sources of polyamine (PA) gene expression based on observations from the prior analysis. We used bulk RNAseq from The Cancer Genome Atlas (TCGA; 10 different cancers) and single cell (sc) RNAseq data from two atlases to parse immune cell contributions to polyamine gene expression. We used TCGA data and an immunotherapy-treated melanoma cohort to examine survival outcomes as a function of polyamine gene set expression. Results: PA metabolism genes were upregulated in aggressive phenotype, T cell-enriched (Thi), HPV+ HNSCs. PA synthesis and transporter gene enrichment was associated with T cell infiltration, recurrent or persistent cancer, overall survival status, primary site, molecular subtype, and MYC genomic alterations. PA synthesis and transport gene sets were more highly expressed in HPV- compared to HPV+ HNSCs. Bulk and scRNAseq data from HPV+ HNSCs demonstrated greater PA catabolism gene set expression among myeloid cells. A combined PA gene set comprised of genes involved in PA synthesis and transport was negatively correlated with cytotoxic T cell functional score across TCGA tumor types. Combined PA gene set expression was associated with greater mortality risk across five tumor types and worse survival in T cell-infiltrated, anti-PD-1-treated melanomas. Conclusions: A genomic approach leveraging T cell-infiltrated, immunogenic HPV+ HNSCs revealed an association between polyamine metabolism, anti-tumor immunity, and prognosis across several cancer types. These data address hurdles to anti-tumor immunity and immunotherapy and warrant further investigation of polyamines as a biomarker for targeted therapy in the context of a T cell-infiltrated microenvironment.

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“…Despite increasing knowledge on T cell memory, many gaps still remain to be filled, especially in respect to TRM, given the relatively recent discovery of these cells. For example, while recirculating memory T cells with phenotype and transcriptional signature similar to hematopoietic stem cells (T stem cell memory cells, TSCM) have been implicated in long-term memory (11)(12)(13), a similar TRM subset has been only partially characterized (14,15). It is also unknown whether TRM residing in different tissues have a diverse longevity (6).…”

Section: Introductionmentioning

confidence: 99%

The Emerging Interplay Between Recirculating and Tissue-Resident Memory T Cells in Cancer Immunity: Lessons Learned From PD-1/PD-L1 Blockade Therapy and Remaining Gaps

et al. 2021

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Remarkable progress has been made in the field of anti-tumor immunity, nevertheless many questions are still open. Thus, even though memory T cells have been implicated in long-term anti-tumor protection, particularly in prevention of cancer recurrence, the bases of their variable effectiveness in tumor patients are poorly understood. Two types of memory T cells have been described according to their traffic pathways: recirculating and tissue-resident memory T cells. Recirculating tumor-specific memory T cells are found in the cell infiltrate of solid tumors, in the lymph and in the peripheral blood, and they constantly migrate in and out of lymph nodes, spleen, and bone marrow. Tissue-resident tumor-specific memory T cells (TRM) permanently reside in the tumor, providing local protection.Anti-PD-1/PD-L1, a type of immune checkpoint blockade (ICB) therapy, can considerably re-invigorate T cell response and lead to successful tumor control, even in patients at advanced stages. Indeed, ICB has led to unprecedented successes against many types of cancers, starting a ground-breaking revolution in tumor therapy. Unfortunately, not all patients are responsive to such treatment, thus further improvements are urgently needed. The mechanisms underlying resistance to ICB are still largely unknown. A better knowledge of the dynamics of the immune response driven by the two types of memory T cells before and after anti-PD-1/PD-L1 would provide important insights on the variability of the outcomes. This would be instrumental to design new treatments to overcome resistance.Here we provide an overview of T cell contribution to immunity against solid tumors, focusing on memory T cells. We summarize recent evidence on the involvement of recirculating memory T cells and TRM in anti-PD-1/PD-L1-elicited antitumor immunity, outline the open questions in the field, and propose that a synergic action of the two types of memory T cells is required to achieve a full response. We argue that a T-centric vision focused on the specific roles and the possible interplay between TRM and recirculating memory T cells will lead to a better understanding of anti-PD-1/PD-L1 mechanism of action, and provide new tools for improving ICB therapeutic strategy.

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Functional HPV-specific PD-1+ stem-like CD8 T cells in head and neck cancer

Cited by 217 publications

References 33 publications

A Tumor-Infiltration CD8+ T Cell-Based Gene Signature for Facilitating the Prognosis and Estimation of Immunization Responses in HPV+ Head and Neck Squamous Cell Cancer

A Tumor-Infiltration CD8+ T Cell-Based Gene Signature for Facilitating the Prognosis and Estimation of Immunization Responses in HPV+ Head and Neck Squamous Cell Cancer

Interrogation of T Cell-Enriched Tumors Reveals Prognostic and Immunotherapeutic Implications of Polyamine Metabolism

The Emerging Interplay Between Recirculating and Tissue-Resident Memory T Cells in Cancer Immunity: Lessons Learned From PD-1/PD-L1 Blockade Therapy and Remaining Gaps

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