Integrating Routine Clinical Factors to Stratify Colorectal Cancer Patients with Liver and Lung Metastases for Immune Therapy

Author(s): Friederike Schlueter, Katharina Doetzer, Martin Pruefer, Alexandr V. Bazhin, Jens Werner, Barbara Mayer

Background: Treatment with checkpoint inhibitors is approved for a small subgroup of mCRC patients with microsatellite instable high (MSI-H) or deficient microsatellite mismatch repair (dMMR) tumors indicating the strong need for additional stratification markers for immune therapy.

Patients and Methods: The immunophenotype (CD3, CD8, PD-1, PD-L1) was immunohistochemically analysed at the invasion margin (IM), the stromal (S) and intratumoral (IT) areas of 53 liver metastases (LM) and 15 lung metastases (LuM), correlated with clinical pathological parameters and statistically evaluated by the Fisher`s exact-Test (two-tailed).

Results: In LM adjuvant chemotherapy resulted in a high CD3+ (p=0.011) and CD8+ (p=0.02) infiltrate at the IM. Neoadjuvant chemotherapy of LM correlated with a reduced PD-L1 expression (p=0.025). LM originating from KRAS wildtype tumors demonstrated a high fraction of CD8+ IT cells (p=0.038) and a strong PD-L1 expression (p=0.03). Locally restricted LM were characterized by a high CD8+ IT infiltrate (unilobular, p=0.019; maximum of 2 segments affected, p=0.038) and were found strongly PD-L1 positive (solitary LM, p=0.02; unilobular, p=0.014; ≤2 liver segments affected, p=0.018). LuM were characterized by a stronger infiltrate of CD3+IT (p=0.005), CD8+S (p=0.021), CD8+IT (p=0.001), PD-1+IM (p=0.007), PD-1+S (p=0.001) and PD-1+IT (p=0.01) compared to LM. In LuM neoadjuvant chemotherapy was accompanied by a high PD-1+IM cell density (p=0.041). Right-sided lesions showed a high infiltrate of CD8+S cells and PD-1+IM cells (p=0.041).

Conclusion: The findings suggest previous chemotherapy, RAS status, tumor burden and sidedness as stratification markers of mCRC patients for immunotherapy, precising treatment management of distant metastases.

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