Mutant KRAS Promotes NKG2D+ T Cell Infiltration and CD155 Dependent Immune Evasion

Abstract Glioblastoma (GBM) is the most common and highly malignant brain tumor in adults. Despite advances in multimodal treatment, GBM remains largely incurable. While immunotherapies have been highly effective in some types of cancer, the disappointing results from clinical trials for GBM immunotherapy represent continued challenges. GBM is highly immunosuppressive and resistant to immunotherapy because of glioma cells escaping from immune surveillance by reprograming the tumor microenvironment (TME). However, understanding the mechanisms of immune evasion by GBM remains elusive. Based on unbiased approaches, we found that Chitinase-3-like-1 (CHI3L1), also known as human homolog YKL-40, is highly expressed in GBM, which is regulated by the CHI3L1-PI3K/AKT/mTOR signaling in a positive feedback loop. Gain- and loss-function studies reveal that CHI3L1 plays a predominant role in regulating an immunosuppressive microenvironment by reprogramming tumor-associated macrophages (TAMs). Using the liquid chromatography-mass spectrometry and orthogonal structure-based screening, we found that Galectin-3 binding protein (Gal3BP) and its binding partner, Galectin-3 (Gal3), can interact competitively with the same binding motif on CHI3L1, leading to selective migration of M2-like versus M1-like bone marrow-derived macrophages (BMDMs) and resident microglia (MG). Mechanistically, the CHI3L1-Gal3 protein complex governs a transcriptional program of NFκB/CEBPβ to control the protumor phenotype of BMDMs, leading to inhibition of T cell infiltration and activation in the GBM TME. However, Gal3BP can reverse CHI3L1-Gal3 induced signaling pathway activation and subsequent protumor phenotype in TAMs. Based on protein binding motifs, a newly developed Gal3BP mimetic peptide can attenuate immune suppression and tumor progression in the syngeneic GBM mouse models, including decreasing M2-like TAMs and increasing M1-like TAMs and T cell infiltration. Together, these results shed light on the role of CHI3L1 protein complexes in immune evasion by glioblastoma and as a potential immunotherapeutic target for this devastating disease.

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The Role of PTEN Loss in Immune Escape, Melanoma Prognosis and Therapy Response

Cancers ◽

10.3390/cancers12030742 ◽

2020 ◽

Vol 12 (3) ◽

pp. 742 ◽

Cited By ~ 2

Author(s):

Rita Cabrita ◽

Shamik Mitra ◽

Adriana Sanna ◽

Henrik Ekedahl ◽

Kristina Lövgren ◽

...

Keyword(s):

T Cell ◽

Metastatic Melanoma ◽

Immune Evasion ◽

Immune Escape ◽

Therapy Response ◽

Predictive Biomarkers ◽

Cell Infiltration ◽

Pten Gene ◽

T Cell Infiltration

Checkpoint blockade therapies have changed the clinical management of metastatic melanoma patients considerably, showing survival benefits. Despite the clinical success, not all patients respond to treatment or they develop resistance. Although there are several treatment predictive biomarkers, understanding therapy resistance and the mechanisms of tumor immune evasion is crucial to increase the frequency of patients benefiting from treatment. The PTEN gene is thought to promote immune evasion and is frequently mutated in cancer and melanoma. Another feature of melanoma tumors that may affect the capacity of escaping T-cell recognition is melanoma cell dedifferentiation characterized by decreased expression of the microphtalmia-associated transcription factor (MITF) gene. In this study, we have explored the role of PTEN in prognosis, therapy response, and immune escape in the context of MITF expression using immunostaining and genomic data from a large cohort of metastatic melanoma. We confirmed in our cohort that PTEN alterations promote immune evasion highlighted by decreased frequency of T-cell infiltration in such tumors, resulting in a worse patient survival. More importantly, our results suggest that dedifferentiated PTEN negative melanoma tumors have poor patient outcome, no T-cell infiltration, and transcriptional properties rendering them resistant to targeted- and immuno-therapy.

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TRIB3 reduces CD8 + T cell infiltration and induces immune evasion by repressing the STAT1-CXCL10 axis in colorectal cancer

Science Translational Medicine ◽

10.1126/scitranslmed.abf0992 ◽

2022 ◽

Vol 14 (626) ◽

Author(s):

Shuang Shang ◽

Yu-wei Yang ◽

Fei Chen ◽

Liang Yu ◽

Shuo-hao Shen ◽

...

Keyword(s):

Colorectal Cancer ◽

T Cell ◽

Immune Evasion ◽

Cd8 T Cell ◽

Cell Infiltration ◽

T Cell Infiltration

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Abstract A085: Immune evasion and PD-1-positive T cell infiltration in DNA mismatch repair-deficient colorectal cancer

10.1158/2326-6066.imm2016-a085 ◽

2016 ◽

Author(s):

Matthias Kloor ◽

Jonas Janikovits ◽

Julia Krzykalla ◽

Axel Benner ◽

Niels Grabe ◽

...

Keyword(s):

Colorectal Cancer ◽

T Cell ◽

Mismatch Repair ◽

Immune Evasion ◽

Dna Mismatch Repair ◽

Cell Infiltration ◽

Dna Mismatch ◽

T Cell Infiltration

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Reversing Epigenetic Gene Silencing to Overcome Immune Evasion in CNS Malignancies

Frontiers in Oncology ◽

10.3389/fonc.2021.719091 ◽

2021 ◽

Vol 11 ◽

Author(s):

Nivedita M. Ratnam ◽

Heather M. Sonnemann ◽

Stephen C. Frederico ◽

Huanwen Chen ◽

Marsha-Kay N. D. Hutchinson ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Growth ◽

Immune Evasion ◽

Immune Cell ◽

Single Agent ◽

Cell Infiltration ◽

Cell Trafficking ◽

T Cell Infiltration ◽

Dismal Prognosis

Glioblastoma (GBM) is an aggressive brain malignancy with a dismal prognosis. With emerging evidence to disprove brain-immune privilege, there has been much interest in examining immunotherapy strategies to treat central nervous system (CNS) cancers. Unfortunately, the limited success of clinical studies investigating immunotherapy regimens, has led to questions about the suitability of immunotherapy for these cancers. Inadequate inherent populations of tumor infiltrating lymphocytes (TILs) and limited trafficking of systemic, circulating T cells into the CNS likely contribute to the poor response to immunotherapy. This paucity of TILs is in concert with the finding of epigenetic silencing of genes that promote immune cell movement (chemotaxis) to the tumor. In this study we evaluated the ability of GSK126, a blood-brain barrier (BBB) permeable small molecule inhibitor of EZH2, to reverse GBM immune evasion by epigenetic suppression of T cell chemotaxis. We also evaluated the in vivo efficacy of this drug in combination with anti-PD-1 treatment on tumor growth, survival and T cell infiltration in syngeneic mouse models. GSK126 reversed H3K27me3 in murine and human GBM cell lines. When combined with anti-PD-1 treatment, a significant increase in activated T cell infiltration into the tumor was observed. This resulted in decreased tumor growth and enhanced survival both in sub-cutaneous and intracranial tumors of immunocompetent, syngeneic murine models of GBM. Additionally, a significant increase in CXCR3+ T cells was also seen in the draining lymph nodes, suggesting their readiness to migrate to the tumor. Closer examination of the mechanism of action of GSK126 revealed its ability to promote the expression of IFN-γ driven chemokines CXCL9 and CXCL10 from the tumor cells, that work to traffic T cells without directly affecting T maturation and/or proliferation. The loss of survival benefit either with single agent or combination in immunocompromised SCID mice, suggest that the therapeutic efficacy of GSK126 in GBM is primarily driven by lymphocytes. Taken together, our data suggests that in glioblastoma, epigenetic modulation using GSK126 could improve current immunotherapy strategies by reversing the epigenetic changes that enable immune cell evasion leading to enhanced immune cell trafficking to the tumor.

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Dihydroartemisinin broke immune evasion through YAP1/JAK1/STAT1, 3 pathways to enhance anti-PD-1 therapy in hepatocellular carcinoma

10.1101/2021.11.30.470572 ◽

2021 ◽

Author(s):

Qing Peng ◽

Shenghao Li ◽

Xinli Shi ◽

Yinglin Guo ◽

Liyuan Hao ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

T Cell ◽

Immune Evasion ◽

Cd8 T Cells ◽

Liver Tumor ◽

Therapeutic Strategy ◽

Cell Infiltration ◽

T Cell Infiltration ◽

Tumor Tissues

The efficacy of anti-PD-1 therapy is not as expected in patients with hepatocellular carcinoma (HCC). Yes-associated protein 1 (YAP1) was overexpressed and activated in HCC. This study aimed to investigate the potential mechanism and inhibitor of YAP1 on immune evasion, and promote anti-PD-1 therapy in HCC. Here, we showed that dihydroartemisinin (DHA), an FDA approved drug, directly suppressed YAP1 expression, leading to break immune evasion in liver tumor niche, characterized by decreased PD-L1 in liver tumor cells and increased CD8+ T cell infiltration. Mechanismly, YAP1 is not only directly related to PD-L1, but also involved in activating the JAK1/STAT1, 3 pathways. Moreover, Yap1 knockout elevated CD4+ and CD8+ T cells in liver tumor niche of Yap1LKO mice. Consistently, verteporfin, YAP1 inhibitor, decreased TGF-β in liver tumor niche and exhausted CD8+ T cells in spleen. Furthermore, DHA combined with anti-PD-1 treatment promoted CD4+ T cell infiltration in the spleen and CD8+ T cells in tumor tissues. Thus, we provide a new combined therapeutic strategy for anti-PD-1 with DHA, a potent YAP1 inhibitor, in HCC.

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