BackgroundImmunotherapy of cancer is successful but tumor regression often is incomplete and followed by escape. Understanding the mechanisms underlying this acquired resistance will aid the development of more effective treatments.MethodsWe exploited a mouse model where tumor-specific therapeutic vaccination results in tumor regression, followed by local recurrence and resistance. In depth studies on systemic, local and tumor intrinsic changes were performed with flow and mass cytometry, immunohistochemistry, transcriptomics and several perturbation studies with inhibitors or agonistic antibodies in mice. Main findings were recapitulated in vaccinated patients.ResultsFull tumor regression and cure of tumor-bearing mice is dependent on the magnitude of the vaccine-induced T-cell response. Recurrence of tumors did not involve classical immune escape mechanisms, such as antigen-presentation alterations, immune checkpoint expression, resistance to killing or local immune suppression. However, the recurrent tumors displayed a changed transcriptome with alterations in p53, tumor necrosis factor-α and transforming growth factor-β signaling pathways and they became immunologically cold. Remarkably, ex vivo cell-sorted recurrent tumors, directly reinjected in naïve hosts retained their resistance to vaccination despite a strong infiltration with tumor-specific CD8+ T cells, similar to that of vaccine-responsive tumors. The influx of inflammatory mature myeloid effector cells in the resistant tumors, however, was impaired and this turned out to be the underlying mechanisms as restoration of inflammatory myeloid cell infiltration reinstated the sensitivity of these refractory tumors to vaccination. Notably, impaired myeloid cell infiltration after vaccination was also associated with vaccine resistance in patients.ConclusionAn immunotherapy-induced disability of tumor cells to attract innate myeloid effector cells formed a major mechanism underlying immune escape and acquired resistance. These data not only stresses the importance of myeloid effector cells during immunotherapy but also demands for new studies to harness their tumoricidal activities.

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Background: Integrin subunit β4 (β4) has been proposed to play an important role in colon cancer progression through its involvement in hemidesmosome disassembly processes and tumor cell migration. However, no consensus has yet been achieved regarding its association with clinical outcomes, particularly in colon cancer. The aim of this study was to reveal the relation between β4 expression and clinicopathological features and colon cancer outcomes.Methods: Expression of β4 was assessed by immunohistochemistry in a large cohort of 651 colon cancer patients, the largest colon cancer cohort so far. Chi-square tests were used to study the association between β4 expression and clinicopathological features while its relation with disease-free survival was assessed by Cox proportional hazard models. Furthermore, a potential relation between levels of ITGB4 expression and patient outcomes was also investigated with the TCGA dataset.Results: No association between β4 expression and disease-free survival was encountered (P = 0.767), which disputes the role of β4 as a biomarker of malignant behavior in colon cancer. Strikingly, loss of β4 expression was instead associated with advanced pathological tumor (pT) stage of the primary tumor. Only 17.9% of the pT1 tumors displayed weak β4 expression level versus 28.1% of pT4 tumors, and 25.0% of the pT1 tumors had a high expression level versus 8.6% of the pT4 tumors (P = 0.012). Additionally, no relation was observed between β4 expression and colon cancer stage (P = 0.138), tumor differentiation grade (P = 0.097) or mismatch repair (MMR) status (P = 0.878).Conclusions: Contradictory reports have suggested opposite roles for β4 expression in (colon) cancer progression. In the present large cohort of colon cancer patients we found that β4 expression was not associated with worse clinical prognosis and tumor differentiation grade, but decreased with advanced pathological tumor stage. Future studies should establish whether loss of β4 expression promotes invasive characteristics of colon cancer cells.

Purpose Integrin subunit β4 (β4) has been proposed to play an important role in colon cancer progression through its involvement in hemidesmosome disassembly processes and tumor cell migration. However, the association between β4 expression and clinicopathological outcomes in colon cancer remains unclear. Methods Expression of β4 was assessed by immunohistochemistry in a large cohort of 651 colon cancer patients, the largest colon cancer cohort so far. Chi-squared tests were used to study the association between β4 expression and clinicopathological features. Overall and disease-free survival were assessed by Cox proportional hazard models. Results Loss of β4 expression was associated with local tumor invasion. Only 17.9% of the pT1 tumors displayed weak β4 expression level versus 28.1% of pT4 tumors, and 25.0% of the pT1 tumors had a high expression level versus 8.6% of the pT4 tumors (p = 0.012). No association between β4 expression and overall (p = 0.845) or disease-free survival (p = 0.767) was encountered, which disputes the role of β4 as a biomarker of malignant behavior in colon cancer. Conclusion Contradictory reports have suggested opposite roles for β4 expression in (colon) cancer progression. In the present large cohort of colon cancer patients, we found that β4 expression was not associated with worse clinical prognosis, but decreased with advanced pathological tumor stage. Future studies should establish whether loss of β4 expression promotes invasive characteristics of colon cancer cells.

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