COX-2 inhibitors decrease expression of PD-L1 in colon tumors and increase the influx of Type I tumor infiltrating lymphocytes

Colorectal cancers (CRCs) deficient in DNA mismatch repair (dMMR) contain abundant CD8+ tumor-infiltrating lymphocytes (TILs) responding to the abundant neoantigens from their unstable genomes. Priming of such tumor-targeted TILs first requires recruitment of CD8+ T cells into the tumors, implying that this is an essential prerequisite of successful dMMR anti-tumor immunity. We have discovered that selective recruitment and activation of systemic CD8+ T cells into dMMR CRCs strictly depend on overexpression of CCL5 and CXCL10 due to endogenous activation of cGAS/STING and type I IFN signaling by damaged DNA. TIL infiltration into orthotopic dMMR CRCs is neoantigen-independent and followed by induction of a resident memory-like phenotype key to the anti-tumor response. CCL5 and CXCL10 could be up-regulated by common chemotherapies in all CRCs, indicating that facilitating CD8+ T cell recruitment underlies their efficacy. Induction of CCL5 and CXCL10 thus represents a tractable therapeutic strategy to induce TIL recruitment into CRCs, where local priming can be maximized even in neoantigen-poor CRCs.

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Presence of tumor-infiltrating lymphocytes is an independent prognostic factor in type I and II endometrial cancer

Gynecologic Oncology ◽

10.1016/j.ygyno.2009.03.022 ◽

2009 ◽

Vol 114 (1) ◽

pp. 105-110 ◽

Cited By ~ 85

Author(s):

R.A. de Jong ◽

N. Leffers ◽

H.M. Boezen ◽

K.A. ten Hoor ◽

A.G.J. van der Zee ◽

...

Keyword(s):

Endometrial Cancer ◽

Prognostic Factor ◽

Tumor Infiltrating Lymphocytes ◽

Independent Prognostic Factor ◽

Type I ◽

Infiltrating Lymphocytes

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Higher Numbers of T-Bet+ Tumor-Infiltrating Lymphocytes Associate with Better Survival in Human Epithelial Ovarian Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000456600 ◽

2017 ◽

Vol 41 (2) ◽

pp. 475-483 ◽

Cited By ~ 5

Author(s):

Yun Xu ◽

Lujun Chen ◽

Bin Xu ◽

Yuqi Xiong ◽

Min Yang ◽

...

Keyword(s):

Ovarian Cancer ◽

Flow Cytometry ◽

Epithelial Ovarian Cancer ◽

Cancer Patients ◽

Tumor Infiltrating Lymphocytes ◽

Lymphoid Cells ◽

Type I ◽

Flow Cytometry Analysis ◽

Cancer Tissues ◽

Infiltrating Lymphocytes

Background/Aims: T-bet, a member of the T-box family of transcription factors, is a key marker of type I immune response within the tumor microenvironment, and has been previously reported by us to serve as an important prognostic indicator for human gastric cancer patients and a potential biomarker for immunotherapy. In the present study, we aimed to assess the clinical significance and prognostic value of T-bet+ tumor-infiltrating lymphocytes in human epithelial ovarian cancer. Methods: The immunohistochemistry was used to analyze the infiltration density of T-bet+ lymphoid cells in human epithelial ovarian cancer tissues, and the flow cytometry analysis was used to further analyze the presence of T-bet+ tumor-infiltrating lymphocytes subgroups in cancer tissues. Results: Our immunohistochemistry analysis showed increased number of T-bet+ lymphoid cells in the human epithelial ovarian cancer tissues, and the flow cytometry analysis further demonstrated the presence of T-bet+ tumor-infiltrating lymphocytes subgroups including CD4+ , CD8+ T cells and NK cells. In addition, we also observed a significant association of T-bet+ tumor-infiltrating lymphocytes density in the tumor nest of cancer with not only serum CA125 levels but also with distant metastasis. However no association was observed with other characteristics like patients' age, pathological type, FIGO stage, tumor site and tumor size. Furthermore, the survival analysis showed that higher density of T-bet+ tumor-infiltrating lymphocytes both in tumor nest and tumor stroma of cancer tissues was significantly associated with better patient survival. In addition, the density of T-bet+ tumor-infiltrating lymphocytes in tumor nest appeared to be an independent risk factor for predicting patients’ postoperative prognoses. Conclusions: Our data indicated that the key transcription factor T-bet might play an important role in the type I immune cells mediated antitumor response, and the density of T-bet+ lymphocytes in human epithelial ovarian cancer tissues could serve as a prognostic predictor for ovarian cancer patients.

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NOS1 inhibits the interferon response of cancer cells by S-nitrosylation of HDAC2

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1448-9 ◽

2019 ◽

Vol 38 (1) ◽

Cited By ~ 4

Author(s):

Pengfei Xu ◽

Shuangyan Ye ◽

Keyi Li ◽

Mengqiu Huang ◽

Qianli Wang ◽

...

Keyword(s):

Rna Polymerase Ii ◽

Lung Metastasis ◽

Molecular Mechanisms ◽

Immune Escape ◽

Tumor Infiltrating Lymphocytes ◽

Interferon Response ◽

Luciferase Reporter ◽

Type I ◽

Mutant Form ◽

Infiltrating Lymphocytes

Abstract Background The dysfunction of type I interferon (IFN) signaling is an important mechanism of immune escape and metastasis in tumors. Increased NOS1 expression has been detected in melanoma, which correlated with dysfunctional IFN signaling and poor response to immunotherapy, but the specific mechanism has not been determined. In this study, we investigated the regulation of NOS1 on the interferon response and clarified the relevant molecular mechanisms. Methods After stable transfection of A375 cells with NOS1 expression plasmids, the transcription and expression of IFNα-stimulated genes (ISGs) were assessed using pISRE luciferase reporter gene analysis, RT-PCR, and western blotting, respectively. The effect of NOS1 on lung metastasis was assessed in melanoma mouse models. A biotin-switch assay was performed to detect the S-nitrosylation of HDAC2 by NOS1. ChIP-qPCR was conducted to measure the binding of HDAC2, H4K16ac, H4K5ac, H3ac, and RNA polymerase II in the promoters of ISGs after IFNα stimulation. This effect was further evaluated by altering the expression level of HDAC2 or by transfecting the HDAC2-C262A/C274A site mutant plasmids into cells. The coimmunoprecipitation assay was performed to detect the interaction of HDAC2 with STAT1 and STAT2. Loss-of-function and gain-of-function approaches were used to examine the effect of HDAC2-C262A/C274A on lung metastasis. Tumor infiltrating lymphocytes were analyzed by flow cytometry. Results HDAC2 is recruited to the promoter of ISGs and deacetylates H4K16 for the optimal expression of ISGs in response to IFNα treatment. Overexpression of NOS1 in melanoma cells decreases IFNα-responsiveness and induces the S-nitrosylation of HDAC2-C262/C274. This modification decreases the binding of HDAC2 with STAT1, thereby reducing the recruitment of HDAC2 to the ISG promoter and the deacetylation of H4K16. Moreover, expression of a mutant form of HDAC2, which cannot be nitrosylated, reverses the inhibition of ISG expression by NOS1 in vitro and decreases NOS1-induced lung metastasis and inhibition of tumor infiltrating lymphocytes in a melanoma mouse model. Conclusions This study provides evidence that NOS1 induces dysfunctional IFN signaling to promote lung metastasis in melanoma, highlighting NOS1-induced S-nitrosylation of HDAC2 in the regulation of IFN signaling via histone modification.

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Tumor-Infiltrating Lymphocytes, Tumor Mutational Burden, and Genetic Alterations in Microsatellite Unstable, Microsatellite Stable, or Mutant POLE/POLD1 Colon Cancer

JCO Precision Oncology ◽

10.1200/po.20.00456 ◽

2021 ◽

pp. 817-826

Author(s):

Ajaratu Keshinro ◽

Chad Vanderbilt ◽

Jin K. Kim ◽

Canan Firat ◽

Chin-Tung Chen ◽

...

Keyword(s):

Colon Cancer ◽

Structural Changes ◽

Transforming Growth Factor ◽

Tumor Infiltrating Lymphocytes ◽

Genetic Alterations ◽

High Power Field ◽

Colon Tumors ◽

Mutational Burden ◽

Tumor Mutational Burden ◽

Infiltrating Lymphocytes

PURPOSE To characterize the relationship between tumor-infiltrating lymphocytes (TIL), tumor mutational burden (TMB), and genetic alterations in microsatellite stable (MSS), microsatellite instability (MSI), or mutant POLE/POLD1 colon cancer. MATERIALS AND METHODS Four hundred ninety-nine resected stage I-III colon tumors treated between 2014 and 2019 were assessed for TIL; somatic mutations, copy number alterations, and structural changes in > 400 oncogenes; and MSI status. RESULTS Of the 499 tumors analyzed, 313 were MSS, 175 were MSI, and 11 had POLE/POLD1 pathogenic mutations. Both the percentage of tumors with a high level of TIL (≥ 4 lymphocytes per high-power field) and the median TMB differed significantly between the three phenotypes: MSS, 4.5% and 6 mutations/Mb; MSI, 68% and 54 mutations/Mb; POLE/POLD1, 82% and 158 mutations/Mb ( P < .05). Within each phenotype, TMB did not vary significantly with TIL level. Among MSI tumors, the median number of frameshift indels was significantly higher in tumors with high levels of TIL (20 v 17; P = .018). In the MSS group, significantly higher proportions of tumors with high levels of TIL had mutations in the transforming growth factor-β (36% v 12%; P = .01), RAS (86% v 54%; P = .02), and Hippo (7% v 1%; P = .046) pathways; in contrast, TP53 alterations were associated with low levels of TIL (74% v 43%; P = .01). CONCLUSION The association between TIL, TMB, and genetic alterations varies significantly between MSI, MSS, and mutant POLE/POLD1 colon tumors. These differences may help explain tumoral immunity and lead to predictors of response to immunotherapy.

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Association of COX-2 expression with lymphocyte infiltration in colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.716 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 716-716

Author(s):

Zehua Wu ◽

Jianwei Zhang ◽

Yue Cai ◽

Liu Yang ◽

Yanhong Deng

Keyword(s):

Colorectal Cancer ◽

Tumor Infiltrating Lymphocytes ◽

High Expression ◽

Lymphocyte Infiltration ◽

Negative Group ◽

Positive Group ◽

High Expression Group ◽

Resected Tumor ◽

Cox 2 ◽

Infiltrating Lymphocytes

716 Background: It is proved that in colorectal cancer, Tumor infiltrating lymphocytes is associated with good prognosis. Someone pointed out that COX inhibitors act with anti-PD-1 antibody in pre-clinical models. This study aims to investigate whether COX-2 expression is associated with lymphocyte infiltration, and to know how they affect the survival. Methods: We collected specimens of resected tumor from patients who received surgery and pathological staging II and III from May 2007 to Jan 2012. These patients received surgery and adjuvant therapy with FOLFOX regimen. Tissue microarrays were made by resected tumor. Immunohistochemical staining was performed with COX-2, CD3 and CD8, PD-1 and PD-L1 antibody. Staining result of COX-2 was measured by two degrees of high and low. For CD3 and CD8, stained lymphocytes in and around tumor tissue were defined stained positive. For PD-1 and PD-L1, more 1% cells stained were defined positive stained. Results: COX-2 expression was correlated with CD3 and CD8.There were more CD3 (63.0% vs. 48.5% p=0.028) and CD8 (95.5% vs. 83.5% p=0.002) expression in the COX-2 high expression group. However, there was no significant difference in PD-1 and PD-L1 expression between COX-2 high and low expression group. As for CD3, PD-1 expression was higher in CD3 positive group than in the negative group (27.6% vs. 10.3% p=0.001). similarly, PD-L1 expression was higher in the CD3 positive group (47.3% vs. 15.2% p < 0.001). but PD-1 and PD-L1 expression was not significantly different between in the CD8 positive and negative group. Three years DFS for the whole group patient was 77.6%. There was a better tendency for 3 years DFS in the CD3 positive group (80.6% vs. 73.7%), but it was not significantly different (p=0.216). Conclusions: CD3 and CD8 expression were more in the COX-2 high expression group, which indicated COX-2 inhibitor use may act with tumor infiltrating lymphocytes. But neither PD-1 nor PD-L1 expression was correlated with COX-2 expression. Infiltrating CD3 lymphocytes may be associated with better DFS for adjuvant chemotherapy colorectal cancer patients. [Table: see text]

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