Prognostic value of CD73 expression in resected colorectal cancer liver metastasis

Immune checkpoint blockade has not yet been effective in patients with mismatch repair proficient metastatic colorectal cancer. Targeting immunosuppressive metabolic pathways is being explored as a new immunotherapeutic approach. We assessed whether CD73, the rate limiting enzyme that catalyzes the degradation of extracellular AMP into immunosuppressive adenosine, could be an immunological determinant of colorectal liver metastases (CRLMs). By immunofluorescence on tissue microarrays, intratumoral CD73 expression (tCD73) was analyzed in 391 CRLMs resected in 215 patients, and soluble CD73 (sCD73) was measured by ELISA in the pre-operative serum of 193 patients. High tCD73 was associated with worse pathological features, such as multiple and larger CRLMs, and poorer pathologic response to pre-operative chemotherapy. The median time to recurrence and disease-specific survival after CRLM resection was significantly shorter in patients with high tCD73 (11.0 and 46.4 months, respectively) compared with low tCD73 (19.0 and 61.5 months, respectively). tCD73 was strongly associated with patient outcomes independently of clinicopathological variables. sCD73 did not correlate with tCD73. Patients with high levels of sCD73 also had shorter disease-specific survival. Our results suggested that CD73 in CRLMs may be prognostically informative and may help select patients more likely to respond to adenosine pathway blocking agents

Prognostic implications of adaptive immune features in MMR-proficient colorectal liver metastases classified by histopathological growth patterns

BACKGROUND: After resection, colorectal cancer liver metastases (CRLM) surrounded by a desmoplastic rim carry a better prognosis than the metastases replacing the adjacent liver. However, these histopathological growth patterns (HGPs) are insufficient to guide clinical decision-making. We explored whether the adaptive immune features of HGPs could refine prognostication. METHODS: From 276 metastases resected in 176 patients classified by HGPs, tissue microarrays were used to assess intratumoral T cells (CD3), antigen presentation capacity (MHC class I) and CD73 expression producing immunosuppressive adenosine. We tested correlations between these variables and patient outcomes. RESULTS: The 101 (57.4%) patients with dominant desmoplastic HGP had a median recurrence-free survival (RFS) of 17.1 months compared to 13.3 months in the 75 patients (42.6%) with dominant replacement HGP (p = 0.037). In desmoplastic CRLM, high vs. low CD73 was the only prognostically informative immune parameter and was associated with a median RFS of 12.3 months compared to 26.3, respectively (p = 0.010). Only in dominant replacement CRLM, we found a subgroup (n = 23) with high intratumoral MHC-I expression but poor CD3(+) T cell infiltration, a phenotype associated with a short median RFS of 7.9 months. CONCLUSIONS: Combining the assessments of HGP and adaptive immune features in resected CRLM could help identify patients at risk of early recurrence