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Hepato-pancreato-biliary

E270: Decreased Primary Tumor Th2 Cell Tumor Infiltration is Associated with Liver Metastases Across Cancer Types

Introduction: Advances in systemic therapy, and particularly immunotherapy, have improved outcomes in metastatic cancer and have led to recognition of an oligometastatic phenotype for certain sites of metastases. As the indications for surgery in oligometastatic disease evolve, it is important to understand the organotropism of different cancers as well as the immune context in which metastases occur. Recent evidence from early phase trials has shown that liver metastases are associated with resistance to immunotherapy, raising the possibility of a unique immune association with this site of spread. We therefore investigated the association of liver metastases with the primary tumor immune microenvironment across cancer types.

Methods: The Cancer Genome Atlas(TCGA) primary clinical databases (gdacv.2016_01_28) were used to develop a comprehensive recurrence dataset  that was correlated with the immune infiltrate signatures (Thorrson, 2018). Immune fractions within the leukocyte population were estimated using CIBERSORT. Genomic and immunologic subtypes were compared to patient outcomes using Welch’s t test and Cox models.

Results: Of the cohort of 10,211 patients from 32 cancer types, 1529 patients had a recurrence recorded.  Of these 1529 recurrences, 843 were distant metastases while 686 were local recurrences. The location of distant metastasis was available for 725 patients(86%) with most(94%) patients having a single site listed. Metastases were present in patients with 22 cancer types with the most common primary sites being skin/soft tissue(n=284), GI(n=211), or GU(n=97) cancers. Patients with liver metastases(mean=-112.2) were found to have lower Th2 cell immune infiltration scores than other sites of recurrence(mean=282; t=8.8, p< 0.001, q=1.12e-16). A sensitivity analysis of cancer subsets revealed the strongest association of Th2 cell infiltration with GI cancers (p < 0.001) when compared to GU and skin/soft tissue. No association with Th2 cell infiltration was noted for metastasis to lung, peritoneum, or brain. Th2 cell infiltration was not associated with survival in the cohort of all patients or all GI patients.

Conclusions: This exploratory study highlights the immune characteristics of primary tumors associated with eventual liver metastases, characterized by significantly lower Th2 cell immune signatures compared to other sites of recurrence. These findings have implications for the surgical management and immunotherapeutic approaches to metastatic cancer patients, particularly in those with liver metastases.

Learning Objectives:

  • Understand the concept of an oligometastatic phenotype in metastatic cancer and its implications for treatment decisions.
  • Explore the role of immune microenvironment and immune cell infiltration in metastatic cancer, specifically in the context of liver metastases.
  • Recognize the potential implications of lower Th2 cell immune signatures in primary tumors associated with liver metastases for the surgical management and immunotherapeutic strategies in metastatic cancer patients.