Dataset Information

Triple Therapy with MerTK and PD1 Inhibition Plus Radiotherapy Promotes Abscopal Antitumor Immune Responses.

ABSTRACT:

Purpose

Radiotherapy (RT) traditionally has been used for local tumor control in the treatment of cancer. The recent discovery that radiotherapy can have anticancer effects on the immune system has led to recognition of its ability to sensitize the tumor microenvironment to immunotherapy. However, radiation can also prompt adverse immunosuppressive effects that block aspects of systemic response at other tumor sites. Our hypothesis was that inhibition of the MER proto-oncogene tyrosine kinase (MerTK) in combination with anti-programmed cell death-1 (?-PD1) checkpoint blockade will enhance immune-mediated responses to radiotherapy.

Experimental design

We tested the efficacy of this triple therapy (Radiation + ?-PD1 + ?-MerTK mAbs) in 129Sv/Ev mice with bilateral lung adenocarcinoma xenografts. Primary tumors were treated with stereotactic radiotherapy (36 Gy in 3 12-Gy fractions), and tumors were monitored for response.

Results

The triple therapy significantly delayed abscopal tumor growth, improved survival rates, and reduced numbers of lung metastases. We further found that the triple therapy increased the activated CD8⁺ and NK cells populations measured by granzyme B expression with upregulation of CD8⁺CD103⁺ tissue-resident memory cells (T_RM) within the abscopal tumor microenvironment relative to radiation only.

Conclusions

The addition of ?-PD1 + ?-MerTK mAbs to radiotherapy could alter the cell death to be more immunogenic and generate adaptive immune response via increasing the retention of T_RM cells in the tumor islets of the abscopal tumors which was proven to play a major role in survival of non-small cell lung cancer patients.

SUBMITTER: Caetano MS

PROVIDER: S-EPMC6911635 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Publications

Triple Therapy with MerTK and PD1 Inhibition Plus Radiotherapy Promotes Abscopal Antitumor Immune Responses.

Caetano Mauricio S MS Younes Ahmed I AI Barsoumian Hampartsoum B HB Quigley Michael M Menon Hari H Gao Chan C Spires Thomas T Reilly Timothy P TP Cadena Alexandra P AP Cushman Taylor R TR Schoenhals Jonathan E JE Li Ailin A Nguyen Quynh-Nhu QN Cortez Maria Angelica MA Welsh James W JW

Clinical cancer research : an official journal of the American Association for Cancer Research 20190920 24

<h4>Purpose</h4>Radiotherapy (RT) traditionally has been used for local tumor control in the treatment of cancer. The recent discovery that radiotherapy can have anticancer effects on the immune system has led to recognition of its ability to sensitize the tumor microenvironment to immunotherapy. However, radiation can also prompt adverse immunosuppressive effects that block aspects of systemic response at other tumor sites. Our hypothesis was that inhibition of the MER proto-oncogene tyrosine k ...[more]

PMID: 31540976

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Project description:BACKGROUND:Distant metastasis is the major cause of mortality in patients with locally advanced rectal cancer (LARC) following neoadjuvant chemoradiotherapy. Local radiotherapy can trigger an abscopal response to metastatic tumor cells. However, the abscopal effect is a rare event. CD4+ regulatory T (Treg) cell is a highly immune-suppressive subset which impedes immune surveillance against cancer, prevents the development of effective antitumor immunity and promotes tumor progression. We assume that the exploitation of the proimmunogenic effects of radiotherapy with anti-CD25 or anti-Cytotoxic T-Lymphocyte Associated Protein 4 (anti-CTLA4) monoclonal antibodies (mAbs) may enhance the local and abscopal effects in rectal cancer and improve the therapeutic outcome. METHODS:mRNA expression profiling of 81 pretreatment biopsy samples from LARC patients who received neoadjuvant radiotherapy (nRT) was performed to analyze the correlation between gene expression and prognosis. A retrospective analysis of patients with rectal cancer with distant metastasis or synchronous extracolonic cancers was performed to evaluate the abscopal effect of radiotherapy on rectal cancer. Two different dual-tumor mouse models were established to investigate the efficacy of single dose and dose-fractionated radiotherapy combined with anti-CD25 or anti-CTLA4 and anti-Programmed cell death 1 ligand 1 (anti-PD1) mAbs on the local tumor growth and liver metastasis. The univariate Cox regression analysis, one-way analysis of variance, Dunnett's test, a mixed-effect linear model and Kaplan-Meier survival analysis were used to calculate p values. RESULTS:The proportion of Tregs in pre-nRT biopsies was negatively correlated with prognosis (p=0.007). The retrospective analysis showed that regressing liver metastases were infiltrated by CD8+ T cells. In contrast, stable/progressing metastases and synchronous extracolonic cancers were characterized by PD1+ T cells and Tregs infiltration. Animal experiment results demonstrated that the combination of radiotherapy and anti-CD25/CTLA4 mAb resulted in a significant increase in CD8+ T cells and CD8+/CD4+ ratio in primary and secondary tumors compared with the irradiation alone group (all p<0.05?or p<0.01). The combined treatment was able to decrease Tregs, PD1+CD8+ and PD1+CD4+ T cells (p<0.05), suppress locally irradiated and distal unirradiated tumor growth, and improve overall survival rate. Radiotherapy in conjunction with anti-CTLA4 reduced liver metastasis (p<0.05). CONCLUSIONS:These data indicated that radiotherapy plus depletion of Tregs was able to improve the antitumor response and generate an abscopal effect.

Dataset Information

Triple Therapy with MerTK and PD1 Inhibition Plus Radiotherapy Promotes Abscopal Antitumor Immune Responses.

Purpose

Experimental design

Results

Conclusions

Publications

Triple Therapy with MerTK and PD1 Inhibition Plus Radiotherapy Promotes Abscopal Antitumor Immune Responses.

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