Triterpenoids of Rhus chinensis Supressed Colorectal Cancer Progress by Enhancing Antitumor Immunity and CD8 + T Cells Tumor Infiltration

BackgroundDespite recent advancements in systemic therapy, only a minority of metastatic patients develop meaningful clinical responses to immune checkpoint inhibitors. Inherent genetic instability of melanoma generates genomically and microenvironmentally distinct metastases. These different tumor microenvironments (TMEs) contain numerous T cell suppression mechanisms, such as upregulation of the PD-1/PD-L1 exhaustion pathway. However, as synchronous metastases share one host immune system, intertumoral heterogeneity may result in increasing cross-talk between metastases that impairs systemic antitumor immunity and promotes PD-1 immunotherapy resistance.MethodsYUMM 1.7 (less immunogenic) and YUMMER 1.7 (more immunogenic cell line derived from YUMM following UVB irradiation) melanoma cell lines were simultaneously injected into opposite flanks of the same mice as a model of synchronous melanoma. We assessed tumor growth in wildtype, interferon-gamma (IFN-γ) knockout, and CD8-depleted mice as well as in response to PD-1 inhibitor. We characterized the TME with flow cytometry and performed TCR sequencing on tumor-infiltrating CD8 T cells.ResultsDistinct TMEs were observed for YUMM and YUMMER tumors simultaneously grown in the same mouse. The presence of the less immunogenic YUMM tumor allows the more immunogenic YUMMER tumors to escape IFN-γ and CD8 T cell-mediated rejection, despite abundant tumor-infiltrating, clonally expanded CD8 T cells. Identical immunodominant CD8 T cell clones were found in both YUMM and YUMMER tumors within the same mouse. Synchronous YUMMER-infiltrating CD8 T cells exhibit suppressed phenotypes, including increased persistence of surface PD-1 and decreased surface CD107a expressions. Simultaneously, these synchronous YUMMER tumors additionally upregulate macrophage surface PD-L1 expression, which potentially contributes to tumor immune escape. Lastly, synchronous YUMMER tumors become resistant to PD-1 inhibition, in direct contrast to control YUMMER tumors.ConclusionsIn a host with multiple melanoma lesions, immunogenicity of all tumors contribute to the systemic antitumor immune response. We show that two synchronous tumors with synonymous mutations (<40%), as is the case with metastatic patients, lead to skewed CD8 T cell expansion of the same clones in both tumors. The presence of a less immunogenic tumor prevents CD8 and IFN-γ mediated rejection of the more immunogenic tumor. Furthermore, CD8 T cells in the more immunogenic tumor exhibit decreased effector function and increased resistance to PD-1 blockade, as tumor-infiltrating macrophages concurrently become more immunosuppressive. These results are highly suggestive of a “reverse abscopal effect,” by which immunologically “cold” tumors generate systemic immunosuppression that facilitate PD-1 immunotherapy resistance and immune escape of all other tumors in synchronous metastatic melanoma patients.AcknowledgementsWe would like to thank Dr. Marcus Bosenberg from the Department of Dermatology at Yale University for kindly gifting us with the YUMMER 1.7 murine melanoma cell line.Ethics ApprovalAnimal experiments were approved by the University Committee on Animal Resources and performed in accordance with University of Rochester approved guidelines.

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CCL5-deficiency enhances intratumoral infiltration of CD8+ T cells in colorectal cancer

Cell Death and Disease ◽

10.1038/s41419-018-0796-2 ◽

2018 ◽

Vol 9 (7) ◽

Cited By ~ 11

Author(s):

Shengbo Zhang ◽

Ming Zhong ◽

Chao Wang ◽

Yanjie Xu ◽

Wei-Qiang Gao ◽

...

Keyword(s):

Colorectal Cancer ◽

T Cells ◽

Cd8 T Cells

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Abstract 4084: NKG2D receptor activation of mTOR and NFκB enhances antitumor immunity in effector CD8+ T cells

10.1158/1538-7445.am2014-4084 ◽

2014 ◽

Author(s):

Emily Whitman ◽

Amorette E. Barber

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Antitumor Immunity ◽

Receptor Activation ◽

Nkg2d Receptor

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MEK Inhibition Acts on CD8+ T Cells to Enhance Antitumor Immunity

Cancer Discovery ◽

10.1158/2159-8290.cd-rw2020-176 ◽

2020 ◽

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Antitumor Immunity ◽

Mek Inhibition

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Prognostic significance of resident CD103+CD8+T cells in human colorectal cancer tissues

Acta Histochemica ◽

10.1016/j.acthis.2019.05.009 ◽

2019 ◽

Vol 121 (5) ◽

pp. 657-663 ◽

Cited By ~ 2

Author(s):

Wenwei Hu ◽

Runzi Sun ◽

Lujun Chen ◽

Xiao Zheng ◽

Jingting Jiang

Keyword(s):

Colorectal Cancer ◽

T Cells ◽

Cd8 T Cells ◽

Prognostic Significance ◽

Human Colorectal Cancer ◽

Cancer Tissues

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Galectin-9 Increases Tim-3+ Dendritic Cells and CD8+ T Cells and Enhances Antitumor Immunity via Galectin-9-Tim-3 Interactions

The Journal of Immunology ◽

10.4049/jimmunol.181.11.7660 ◽

2008 ◽

Vol 181 (11) ◽

pp. 7660-7669 ◽

Cited By ~ 119

Author(s):

Keiko Nagahara ◽

Tomohiro Arikawa ◽

Souichi Oomizu ◽

Keiichi Kontani ◽

Atsuya Nobumoto ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd8 T Cells ◽

Antitumor Immunity

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Association between gut microbiome and T lymphocytes among different primary tumor sites of patients with metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16013 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16013-e16013

Author(s):

Lingyun Sun ◽

Yunzi Yan ◽

Dongmei Chen ◽

Jun J. Mao ◽

Yufei Yang

Keyword(s):

Colorectal Cancer ◽

T Cells ◽

T Lymphocytes ◽

Cd8 T Cells ◽

Primary Tumor ◽

Principal Component ◽

Alpha Diversity ◽

T Lymphocyte Subsets ◽

Cell Immunity ◽

Xiyuan Hospital

e16013 Background: Different primary tumor sites could impact colorectal cancer (CRC)’s survival outcomes and treatment effects. Previous studies had found that gut micro-biome distributions were different between left and right colon cancer(LCC, RCC). Out study aimed to further investigate the association between micro-biome and T lymphocytes among different tumor sites of patients with metastatic CRC. Methods: Between April 2018 and Mars 2019, we enrolled 40 metastatic CRC patients in Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China. We collected patients’ stool samples for micro-biome analysis by 16s rRNA sequencing approaches, as well as patients’ blood samples to analyses T lymphocyte subsets by flow cytometry methods. The study had been proved by ethics committee of Xiyuan Hospital (2016XLA122-1). All patients consented before enrollment. Results: Among 40 patients, 28% were female, with average age of 63±15 years old. There were 10 RCC, 9 LCC and 21 rectal cancer(RC) patients. Alpha diversity analysis showed that sobs index of the micro-biome of patients with RC and RC was significantly higher than whom were RCC(254.89±99, 247±89 versus.[vs.]101.17±51, p= 0.001). PCoA analysis on OTU level detected that first principal component[PC1] (26.24%) could be separated significantly between RCC and LCC( p= 0.048), as well as between RC and RCC (PC1,14.17%, p= 0.024). Community analysis showed that the proportion of Bacteroidetes was significantly higher in patients with RCC than whom with LCC and RC( p= 0.009). Conversely, the proportion of Firmicutes, Proteobacteria and Verrucomicrobia were higher in LCC patients than others( p= 0.37, 0.047 and 0.032 respectively). Canonical Correlation Analysis (CCA) analysis proved that the CD4+ and CD8+ T cells counts were environmental factors, which were significantly associated with certain micro-biome and samples from different tumor sites( p= 0.037 and 0.01 respectively). Trends showed that CD4+ T cells were positively related with samples of RC and bacteria parabacteroides and bifidobacterium, while CD8+ T cells were positively related with samples of RCC and bacteria Lachnospira, Sutterella and Bacteroides. Conclusions: In our study, we found that patients with LCC and RC had more beneficial gut micro-biome than whom with RCC. In addition, such difference might be associated with body T cell immunity.

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