Anti-PD-1 elicits regression of undifferentiated pleomorphic sarcomas with UV-mutation signatures

Undifferentiated pleomorphic sarcoma (UPS), an aggressive soft-tissue sarcoma of adults, has been characterized by low tumor mutational burden (TMB) and high copy number alterations. Clinical trials of programmed death-1 (PD-1) blockade in UPS have reported widely varying efficacy. We describe two patients with recurrent scalp UPS that experienced clinical benefit from PD-1 blockade. These tumors had high TMB with a UV-induced mutational pattern. Analysis of additional head and neck UPS cases identified five out of seven tumors with high TMB and an ultraviolet (UV) mutational signature. Head and neck UPS tumors also had increased programmed death-ligand 1 (PD-L1) expression and CD8+ T cell infiltration as compared with UPS tumors arising from other sites. In summary, we found that UPS tumors of the head and neck, but not elsewhere, have a PD-L1+, T-cell-inflamed tumor microenvironment and high TMB, suggesting that these tumors represent a distinct genetic subgroup of UPS for which immune checkpoint inhibitor therapy might be effective.

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Activation of memory/effector T cells and association between prognosis and OX40-positive T cells in advanced head and neck cancer patients treated with anti-programmed death-1 antibody.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.5_suppl.35 ◽

2020 ◽

Vol 38 (5_suppl) ◽

pp. 35-35

Author(s):

Hirofumi Ohmura ◽

Kyoko Yamaguchi ◽

Fumiyasu Hanamura ◽

Tanoue Kenrou ◽

Shiho Kawagoe ◽

...

Keyword(s):

T Cells ◽

Head And Neck Cancer ◽

T Cell ◽

Head And Neck ◽

Neck Cancer ◽

Cd8 T Cells ◽

Central Memory ◽

Advanced Head ◽

Programmed Death ◽

Programmed Death 1

35 Background: Anti-programmed death-1 (PD-1) monoclonal antibody, nivolumab, enhances anti-tumor activity by inhibiting the interaction of PD-1 and programmed death-1 ligand 1 and has shown efficacy for platinum-refractory recurrent or advanced head and neck cancer (HNC). However, subsets of immune cells predominantly activated during the period of anti-PD-1 therapy for HNC and specifically associated with the prognosis have not been clarified. Methods: Peripheral blood mononuclear cells of 15 HNC patients treated with nivolumab were prospectively obtained before the initial and second administrations of nivolumab, and at the time of progressive disease (PD). We performed comprehensive analysis of the proportion of immune cell subsets by flow cytometry, including the expression of coinhibitory and costimulatory molecules such as T-cell immunoglobulin and mucin domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), B and T lymphocyte attenuator (BTLA), CD28, OX40, inducible T cell costimulator (ICOS). Association between changes in the proportion of the subsets and therapeutic effect were also analyzed. Results: Median progression free survival (PFS) of the whole patients was 96 days (95% CI 70–308). After a single course of nivolumab, patients showed a significant increase in activated central memory and effector subsets of CD4+/CD8+ T cells and activated helper T1 cells (p = 0.0039, 0.0078, 0.0273, 0.0391, 0.0391). A trend of increase of activated effector memory CD4+/CD8+ T cell was observed (p = 0.4961, 0.3594). At the time of PD, effector regulatory T cells, LAG3 positive CD4+/CD8+ T cells, TIM-3 positive CD4+/CD8 T cells and BTLA positive CD4+/CD8+ T cells significantly increased. Significant positive correlations were found between PFS and the proportion of OX40 positive CD4+/CD8+ T cells before nivolumab therapy (p = 0.0239, 0.0134). Conclusions: Nivolumab therapy enhances activation of central memory and effector subsets of CD4+/CD8+ T cells. The expression level of OX40 on T cells was correlated with efficacy of nivolumab therapy in HNC patients.

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Clinical significance of programmed death 1 ligand-1 (CD274/PD-L1) and intra-tumoral CD8+ T-cell infiltration in stage II–III colorectal cancer

Scientific Reports ◽

10.1038/s41598-018-33927-5 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 12

Author(s):

Chih-Yang Huang ◽

Shu-Fen Chiang ◽

Tao-Wei Ke ◽

Tsung-Wei Chen ◽

Ying-Shu You ◽

...

Keyword(s):

Colorectal Cancer ◽

T Cell ◽

Clinical Significance ◽

Cd8 T Cell ◽

Stage Ii ◽

Cell Infiltration ◽

T Cell Infiltration ◽

Programmed Death ◽

Programmed Death 1

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Author response for "CD8+CD73+ T cells in the tumor microenvironment of head and neck cancer patients are linked to diminished T cell infiltration and activation in tumor tissue"

10.1002/eji.202048626/v2/response1 ◽

2020 ◽

Author(s):

Soumya Panigrahi ◽

Douglas A. Bazdar ◽

Marwah Albakri ◽

Brian Ferrari ◽

Christopher J. Antonelli ◽

...

Keyword(s):

T Cells ◽

Head And Neck Cancer ◽

T Cell ◽

Tumor Microenvironment ◽

Head And Neck ◽

Cancer Patients ◽

Neck Cancer ◽

Tumor Tissue ◽

Author Response ◽

T Cell Infiltration

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Review for "CD8+CD73+ T cells in the tumor microenvironment of head and neck cancer patients are linked to diminished T cell infiltration and activation in tumor tissue"

10.1002/eji.202048626/v1/review2 ◽

2020 ◽

Keyword(s):

T Cells ◽

Head And Neck Cancer ◽

T Cell ◽

Tumor Microenvironment ◽

Head And Neck ◽

Cancer Patients ◽

Neck Cancer ◽

Tumor Tissue ◽

Cell Infiltration ◽

T Cell Infiltration

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Faculty Opinions recommendation of Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1088493.541560 ◽

2007 ◽

Author(s):

P'ng Loke

Keyword(s):

T Cell ◽

Costimulatory Molecule ◽

T Cell Responses ◽

Cell Responses ◽

Programmed Death ◽

Programmed Death 1

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Immunotherapy Predictive Molecular Markers in Advanced Gastroesophageal Cancer: MSI and Beyond

Cancers ◽

10.3390/cancers13071715 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1715

Author(s):

Robin Park ◽

Laercio Lopes ◽

Anwaar Saeed

Keyword(s):

Treatment Options ◽

Unmet Need ◽

Predictive Biomarkers ◽

Phase Iii ◽

Gastroesophageal Cancer ◽

Programmed Death ◽

Phase Iii Trials ◽

Tumor Mutational Burden ◽

Large Phase ◽

Programmed Death 1

Advanced gastroesophageal cancer (GEC) has a poor prognosis and limited treatment options. Immunotherapy including the anti-programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab have been approved for use in various treatment settings in GEC. Additionally, frontline chemoimmunotherapy regimens have recently demonstrated promising efficacy in large phase III trials and have the potential to be added to the therapeutic armamentarium in the near future. There are currently several immunotherapy biomarkers that are validated for use in the clinical setting for GEC including programmed death ligand-1 (PD-L1) expression as well as the tumor agnostic biomarkers such as mismatch repair or microsatellite instability (MMR/MSI) and tumor mutational burden (TMB). However, apart from MMR/MSI, these biomarkers are imperfect because none are highly sensitive nor specific. Therefore, there is an unmet need for immunotherapy biomarker development. To this end, several biomarkers are currently being evaluated in ongoing trials with some showing promising predictive potential. Here, we summarize the landscape of immunotherapy predictive biomarkers that are currently being evaluated in GEC.

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