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74 Tumor microenvironment based on PD-L1 and CD8 T-cell infiltration correlated with the response of MSS mCRC patients treated vactosertib in combination with pembrolizumab
  1. Tae Won Kim1,
  2. Keun-Wook Lee2,
  3. Joong Bae Ahn3,
  4. Young Suk Park4,
  5. Chan-Young Ock5,
  6. Hyejoo Park5,
  7. Jiyeon Ryu5,
  8. Bitna Oh5,
  9. Bo-Kyoung Kim5,
  10. Sunjin Hwang5,
  11. Ki Baik Hahm5 and
  12. Seong-Jin Kim5
  1. 1Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, Republic of
  2. 2Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea, Republic of
  3. 3Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea, Republic of
  4. 4Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic of
  5. 5MedPacto, Inc., Seoul, Korea, Republic of


Background The expression of PD-L1 and tumor-infiltrating CD8 T cells were reported to have a decisive effect on the immunotherapy response (PMID: 26819449). Microsatellite stable (MSS) metastatic colorectal cancer (mCRC) shows a limited clinical benefit to immunotherapy alone known to be having an ‘immune-cold’ microenvironment. To understand the basis of the clinical responses to anti-PD-1 and TGF-β inhibitor combination therapy in MSS mCRC, we conducted a comprehensive analysis of survival outcome, whole transcriptome sequencing (WTS) data, and multiplex immunohistochemistry (mIHC) data from a combination treatment of vactosertib and pembrolizumab.

Methods Clinical outcomes were evaluated by RECIST v1.1 and iRECIST. Tumor tissue biopsy samples for WTS and mIHC were obtained in screening and cycle 2 post-treatment time point. CD274(PD-L1) and CD8A expression cut-off were calculated as a median value in the merged data set of TCGA Pan-cancer and MP-VAC-204 study. Having over median value defined as a high group and under median value as a low group. Tumor immune status by a combination of gene expression (high or low) was classified into four subtypes (1: CD274 high, CD8A high; 2: CD274 low, CD8A low; 3: CD274 high, CD8A low; 4: CD274 low, CD8A high). Tumor tissue slides stained with PD-L1, CD8, and granzyme B (GZB) in tumor nest and stroma.

Results Among 43 patients whose WTS data are available, thus included in the analysis, 9 patients were responders (7 PRs and 2 iPRs). Subtype 2 showed a major proportion in the MP-VAC-204 CRC patients (1: 14%, 2: 58%, 3: 12%, 4: 16%). Responders were observed in subtype 2 and 4 (24% and 14%, RECIST). The CD8A expression and median overall survival (mOS) showed a significantly positive correlation (**P=0.0028) and there was no significance in the correlation of CD274 and mOS. mOS was significantly longer in high expression of CD8A patients (*P=0.0083, Not reached vs 9.9 months, hazard ratio 8.812 [95% CI 3.19–24.31]). After the combination treatment, CD8 and GZB positive T cells were increased significantly in both tumor nest and stroma.

Conclusions Our study suggests a high level of CD8 T cells, even in the case of low PD-L1 expression, is significantly correlated with the improved clinical outcomes in MSS mCRC patients treated with vactosertib and pembrolizumab. The increases in CD8 T cells both in tumor nest and stroma after the combined inhibition of PD-1 and TGF-β pathway may contribute to the survival benefit. Further clinical investigations are warranted. (Clinical trial information: NCT03724851)

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