Differential T‐cell subset representation in cutaneous squamous cell carcinoma arising in immunosuppressed versus immunocompetent individuals

Feldmeyer, Laurence; Ching, Grace; Vin, Harina; Ma, Wencai; Bansal, Varun; Chitsazzadeh, Vida; Jahan‐Tigh, Richard R.; Chu, Emily Y.; Fuller, Peter J.; Maiti, Sourindra N.; Davis, R. Eric; Cooper, Laurence J.N.; Tsai, Kenneth Y.

doi:10.1111/exd.12878

Cited by 7 publications

(14 citation statements)

References 13 publications

(13 reference statements)

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“…18,[39][40][41] A previous study revealed that the Treg-to-CD8 + T cell ratio in IS transplant patients was significantly higher than that in IC patients. 42,43 In the present study, we found that organ transplant patients had decreased global number of Tregs compared with IC patients. This aligns with the T cellsuppressive effects of the calcineurin inhibitors tacrolimus and cyclosporin as well as those of mycophenolic mofetil, the mainstays of immunosuppressive therapy in the organ transplant population.…”

Section: Discussionsupporting

confidence: 57%

The Tumor Microenvironment of Cutaneous Squamous Cell Carcinoma in Immunosuppressed Patients

Amit

Gleber‐Netto

Nagarajan

et al. 2021

Preprint

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Nonmelanoma skin cancer is the most common malignancy and immunosuppression is a key risk factor. Despite the promising data demonstrating the efficacy of immune checkpoint inhibition in the treatment of cutaneous squamous cell carcinoma (cSCC), most immunosuppressed patients are not included in immunotherapy trials due to the risk for toxicity and the lack of data regarding cSCC immune landscape in immunosuppressed patients. To characterize the specific alterations accounting for a diminished antitumor immune response in immunosuppressed patients, we used multispectral imaging on cSCC pathology specimens from immunosuppressed patients with age and stage matched immunocompetent controls. We show that densities of CD68+ cells are diminished in immunosuppressed patients. Moreover, using an organ transplant recipient cohort from two cancer centers, we found significantly lower effector T-cells densities as compared with controls. Overall, density of CD68+ and CD8+LAG3+ cells were predictors of disease-specific and disease-free survival. These findings provide insight into the patterns of immune infiltrating cells in patients with different types of immunosuppression; leading us to conjecture that different immune based therapeutic approaches may be needed to treat immunosuppressed cSCC patients.

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Section: Discussionsupporting

confidence: 57%

The Tumor Microenvironment of Cutaneous Squamous Cell Carcinoma in Immunosuppressed Patients

Amit

Gleber‐Netto

Nagarajan

et al. 2021

Preprint

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“…In our study, the tumoral Tregs were the T cell subset that expressed OX40 at the highest frequencies, consistent with observations from studies on murine tumors which used anti-OX40 antibodies to deplete intratumoral Tregs and enhance anti-tumor immunity (16–18), suggesting a similar strategy could be beneficial in cSCC. OX40 has been demonstrated on CD4 + tumor-infiltrating lymphocytes in melanoma and head and neck cancer (47), and whereas a recent study has documented the presence of OX40 expressing lymphocytes in cSCC (48), our work highlights that this molecule is predominantly expressed by Tregs in this cancer. Furthermore, our study shows that higher percentages of tumor infiltrating lymphocytes express OX40 in primary metastasizing cSCCs compared with primary tumors which had not metastasized.…”

Section: Discussionmentioning

confidence: 46%

OX40+ Regulatory T Cells in Cutaneous Squamous Cell Carcinoma Suppress Effector T-Cell Responses and Associate with Metastatic Potential

Lai

August

Albibas

et al. 2016

Clinical Cancer Research

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Purpose Cutaneous squamous cell carcinoma (cSCC) is the most common human cancer with metastatic potential. Despite T cells accumulating around cSCCs, these tumors continue to grow and persist. To investigate reasons for failure of T cells to mount a protective response in cSCC, we focused on regulatory T cells (Tregs) as this suppressive population is well represented among the infiltrating lymphocytes. Experimental Design Flow cytometry was conducted on cSCC lymphocytes and in vitro functional assays were performed using sorted tumoral T cells. Lymphocyte subsets in primary cSCCs were quantified immunohistochemically. Results FOXP3+ Tregs were more frequent in cSCCs than in peripheral blood (p<0.0001, n=86 tumors). Tumoral Tregs suppressed proliferation of tumoral effector CD4+ (p=0.005, n=10 tumors) and CD8+ T cells (p=0.043, n=9 tumors) and inhibited interferon-γ secretion by tumoral effector T cells (p=0.0186, n=11 tumors). The costimulatory molecule OX40 was expressed predominantly on tumoral Tregs (p<0.0001, n=15 tumors) and triggering OX40 with an agonist anti-OX40 antibody overcame the suppression exerted by Tregs, leading to increased tumoral effector CD4+ lymphocyte proliferation (p=0.0098, n=10 tumors). Tregs and OX40+ lymphocytes were more abundant in primary cSCCs which metastasized than in primary cSCCs which had not metastasized (n=48 and n=49 tumors respectively). Conclusions Tregs in cSCCs suppress effector T cell responses and are associated with subsequent metastasis, suggesting a key role for Tregs in cSCC development and progression. OX40 agonism reversed the suppressive effects of Tregs in vitro, suggesting that targeting OX40 could benefit the subset of cSCC patients at high risk of metastasis.

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“…In addition to the more traditional immunological techniques, Feldmeyer et al (8), have explored the use of a novel molecular technique, NanoString â , to compare the T-cell phenotype in SCC lesions collected from immunosuppressed and immunocompetent patients. NanoString â is a new platform available for quantifying the expression of up to 800 preselected genes.…”

Section: Accepted For Publication 11 April 2016mentioning

confidence: 99%

Assessing T‐cell abundance in cutaneous squamous cell carcinoma: adding another string to your bow

Cruz

Wells

2016

Experimental Dermatology

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Differential T‐cell subset representation in cutaneous squamous cell carcinoma arising in immunosuppressed versus immunocompetent individuals

Abstract: Abbreviations: cuSCC, cutaneous squamous cell carcinoma; FOXO1, forkhead box protein O1; OTR, organ transplant recipients; Treg, regulatory T cells.

Cited by 7 publications

References 13 publications

The Tumor Microenvironment of Cutaneous Squamous Cell Carcinoma in Immunosuppressed Patients

The Tumor Microenvironment of Cutaneous Squamous Cell Carcinoma in Immunosuppressed Patients

OX40+ Regulatory T Cells in Cutaneous Squamous Cell Carcinoma Suppress Effector T-Cell Responses and Associate with Metastatic Potential

Assessing T‐cell abundance in cutaneous squamous cell carcinoma: adding another string to your bow

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