Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy

Luoma, Adrienne; Suo, Shengbao; Wang, Yifan; Gunasti, Lauren; Porter, Caroline; Nabilsi, Nancy H.; Tadros, Jenny; Ferretti, Andrew P.; Liao, Sida; Gurer, Cagan; Chen, Yuhui; Criscitiello, Shana; Ricker, Cora A.; Dionne, Danielle; Rozenblatt-Rosen, Orit; Uppaluri, Ravindra; Haddad, Robert I.; Ashenberg, Orr; Regev, Aviv; Allen, Eliezer M. Van; MacBeath, Gavin; Schoenfeld, Jonathan D.; Wucherpfennig, Kai W.

doi:10.1016/j.cell.2022.06.018

Cited by 136 publications

(124 citation statements)

References 87 publications

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“…Moreover, recent studies demonstrated that the T RM cell subset increases in responder patients with non-small cell lung cancer (NSCLC) and melanoma upon anti-PD-1 administration [44,45]. Interestingly, data from HNSCC patients treated with neoadjuvant immunotherapy (nivolumab as monotherapy or in combination with ipilimumab) demonstrated that ICI-fostered early intra-tumoral responses are primarily mediated by pre-existing T cell populations with a T RM gene program, which is characterized by tissue residency, cytotoxicity, effector functions and inhibitory receptors including PD-1 [46]. Moreover, authors showed that neoadjuvant ICI can enhance both local and systemic tumor immunity, as they found treatment-induced expansion of emergent T cell clones in tumors and in the peripheral blood, which were undetectable prior to therapy [46].…”

Section: Discussionmentioning

confidence: 99%

The immune microenvironment of HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma: a multiparametric quantitative and spatial analysis unveils a rationale to target treatment-naïve tumors with immune checkpoint inhibitors

Tosi

Parisatto

Menegaldo

et al. 2022

J Exp Clin Cancer Res

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Background Immune checkpoint inhibitors (ICI) are approved for treatment of recurrent or metastatic oropharyngeal head and neck squamous cell carcinoma in the first- and second-line settings. However, only 15–20% of patients benefit from this treatment, a feature increasingly ascribed to the peculiar characteristics of the tumor immune microenvironment (TIME). Methods Immune-related gene expression profiling (GEP) and multiplex immunofluorescence (mIF) including spatial proximity analysis, were used to characterize the TIME of 39 treatment-naïve oropharyngeal squamous cell carcinomas (OPSCC) and the corresponding lymph node metastases. GEP and mIF results were correlated with disease-free survival (DFS). HPV-positive tumors disclosed a stronger activation of several immune signalling pathways, as well as a higher expression of genes related to total tumor-infiltrating lymphocytes, CD8 T cells, cytotoxic cells and exhausted CD8 cells, than HPV-negative patients. Accordingly, mIF revealed that HPV-positive lesions were heavily infiltrated as compared to HPV-negative counterparts, with a higher density of T cells and checkpoint molecules. CD8+ T cells appeared in closer proximity to tumor cells, CD163+ macrophages and FoxP3+ cells in HPV-positive primary tumors, and related metastases. In HPV-positive lesions, PD-L1 expression was increased as compared to HPV-negative samples, and PD-L1+ tumor cells and macrophages were closer to PD-1+ cytotoxic T lymphocytes. Considering the whole cohort, a positive correlation was observed between DFS and higher levels of activating immune signatures and T cell responses, higher density of PD-1+ T cells and their closer proximity to tumor cells or PD-L1+ macrophages. HPV-positive patients with higher infiltration of T cells and macrophages had a longer DFS, while CD163+ macrophages had a negative role in prognosis of HPV-negative patients. Conclusions Our results suggest that checkpoint expression may reflect an ongoing antitumor immune response. Thus, these observations provide the rationale for the incorporation of ICI in the loco-regional therapy strategies for patients with heavily infiltrated treatment-naïve OPSCC, and for the combination of ICI with tumor-specific T cell response inducers or TAM modulators for the “cold” OPSCC counterparts.

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Section: Discussionmentioning

confidence: 99%

The immune microenvironment of HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma: a multiparametric quantitative and spatial analysis unveils a rationale to target treatment-naïve tumors with immune checkpoint inhibitors

Tosi

Parisatto

Menegaldo

et al. 2022

J Exp Clin Cancer Res

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“…Due to a number of restrictions and other factors, many current TIL studies only roughly identify the antitumor type of T cells based on some biological traits of Neo T cells, such as higher levels of exhausted status and expansion, which is detrimental to the in-depth study of the biological mechanism of T cells in anti-tumor immunity (31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

A machine learning model that identifies neoantigen-reactive CD8+ T cells in human gastrointestinal cancer

Shi

2022

Preprint

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It appears that tumor-infiltrating neoantigen-reactive CD8 + T cells are the primary driver of immune responses to gastrointestinal cancer in patients. By mapping neoantigen-reactive T cells from the single-cell transcriptomes of thousands of tumor-infiltrating lymphocytes, we developed a 26-gene machine learning model for the identification of neoantigen-reactive T cells. In both training and test sets, the model performed admirably. We discovered, by applying the model to large-scale single-cell sequencing data of tumor-infiltrating CD8 + T cells, that Neo T cells exhibited a hyperexpanded phenotype and two distinct differentiation pathways. Moreover, compared to non-neoantigen-reactive T cells, the majority of neoantigen-reactive T cells exhibited notable differences in the biological processes of locomotion and amide metabolism. The analysis of potential cell-to-cell interactions revealed that neoantigen-reactive T cells contain potent signaling molecules, such as CXCL13 and LTA, associated with the formation of tertiary lymphoid structures. This method expedites the identification of neoantigen-reactive TCRs and the engineering of neoantigen-reactive T cells for therapy.

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“…Eomes expression increases over time as CD8 + T cells undergo differentiation from naïve CD8 + T cells to T EM and maintain homeostasis via IL-15 signaling ( 60 ). In T RM however, Eomes expression is completely suppressed, as it is the KLRG1 - CD127 + precursors that give rise to T RM ( 61 ). This was demonstrated experimentally in a murine model of HSV where Mackay et al.…”

Section: Hallmarks Of Tissue-resident Memory T Cellsmentioning

confidence: 99%

Tissue-resident memory T cells in the era of (Neo) adjuvant melanoma management

et al. 2022

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Tissue-resident memory T (TRM) cells have emerged as key players in the immune control of melanoma. These specialized cells are identified by expression of tissue retention markers such as CD69, CD103 and CD49a with downregulation of egress molecules such as Sphingosine-1-Phosphate Receptor-1 (S1PR1) and the lymphoid homing receptor, CD62L. TRM have been shown to be integral in controlling infections such as herpes simplex virus (HSV), lymphocytic choriomeningitis virus (LCMV) and influenza. More recently, robust pre-clinical models have also demonstrated TRM are able to maintain melanoma in a dormant state without progression to macroscopic disease reminiscent of their ability to control viral infections. The discovery of the role these cells play in anti-melanoma immunity has coincided with the advent of immune checkpoint inhibitor (ICI) therapy which has revolutionized the treatment of cancers. ICIs that target programmed death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) have led to substantial improvements in outcomes for patients with metastatic melanoma and have been rapidly employed to reduce recurrences in the resected stage III setting. While ICIs mediate anti-tumor activity via CD8+ T cells, the specific subsets that facilitate this response is unclear. TRM invariably exhibit high expression of immune checkpoints such as PD-1, CTLA-4 and lymphocyte activating gene-3 (LAG-3) which strongly implicates this CD8+ T cell subset as a crucial mediator of ICI activity. In this review, we present pre-clinical and translational studies that highlight the critical role of TRM in both immune control of primary melanoma and as a key CD8+ T cell subset that mediates anti-tumor activity of ICIs for the treatment of melanoma.

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Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy

Cited by 136 publications

References 87 publications

The immune microenvironment of HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma: a multiparametric quantitative and spatial analysis unveils a rationale to target treatment-naïve tumors with immune checkpoint inhibitors

The immune microenvironment of HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma: a multiparametric quantitative and spatial analysis unveils a rationale to target treatment-naïve tumors with immune checkpoint inhibitors

A machine learning model that identifies neoantigen-reactive CD8+ T cells in human gastrointestinal cancer

Tissue-resident memory T cells in the era of (Neo) adjuvant melanoma management

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