Enhancement of anti-tumor immunity and survival prolongation by neoadjuvant 5-FU, oxaliplatin and irinotecan (folfirinox) in pancreatic ductal adenocarcinoma patients

Abstract

Background: Due to the encouraging results in the metastatic setting, patients with locally advanced PDAC (LA PDAC) have been treated with FOLFIRINOX, often followed by radiation, with the hope of getting them to resection. Our aim was to characterize the immunological profile of the tumor microenvironment, by analyzing: i) the expression of HLA antigens by PDAC cells, since these molecules play a crucial role in the interactions of tumor cells with host’s immune system and ii) the infiltration of tumors by immune cells which has been shown to reflect patients’ antitumor immune response in the tumor microenvironment. Methods: Clinicopathologic data were collected from 63 FOLFIRINOX treated patients between 2012 and 2014, 18 photon patients (50.4Gy) between 1998 and 2010 and 154 no neoadjuvant patients between 1998 and 2012. Immunohistochemical staing was performed for HLA-A, HLA-B, HLA-C, CD8, CD4, and FoxP3. Results: Of the 235 patients the median age was 66 yo and 50% were women. Immunohistochemical staining demonstrated defects in both HLA-A and HLA-B and C expression in more than 60% of the PDACs analyzed the frequency of HLA-A defects in PDACs from FOLFIRINOX patients was significantly lower than in tumors from the other two cohorts (p = 0.001). Both CD8 + and CD4 + T cell density in tumors from FOLFIRINOX patients was significantly higher than that in tumors from photon and no neoadjuvant patients. FoxP3 + cell density in PDACs from FOLFIRINOX patients was significantly lower than that in tumors from photon and no neoadjuvant patients (p = 0.001). In the FOLFIRINOX cohort CD8 + T cell density, but not CD4 + , correlated with HLA-A expression (p < 0.001). Conclusion: FOLFIRINOX increases the expression of HLA class I and the immune infiltrate. The altered immune microenvironment may make FOLFIRINOX an attractive therapy to combine with an immune modulator in PDAC.TableResults of immunohistochemical staining of 218 surgically removed PDACs treated with neoadjuvant FOLFIRINOX alone or followed by radiotherapy (photon or proton) (n = 63), photon radiotherapy (n = 18) and no neoadjuvant therapy (n = 137)FOLFIRINOX +/− proton or photon radiationPhoton radiationNo neoadjuvantOverallp-valueCells/HPF medianIQRCells/HPF medianIQRCells/HPF medianIQRCells/HPF medianIQRFoxP3+10–231–431–521–4<0.001CD8+4024–8071–15179–302111–37<0.001N%N%N%N%HLA-A0.001 Negative11.6527.82317.63313.7 Heterogeneous3758.71161.17658.014660.3 Positive2539.7211.13224.46326.0HLA-B/C0.855 Negative57.915.664.6145.8 Heterogeneous3555.61161.17255.413857.3 Positive2336.5633.35240.08936.9HPF: high Power Field; IQR: inter-Quartile Range. p-values derived from Fisher's exact test or Kruskal Wallis test, as appropriate. Staining was not obtained for all slides for all markers (that is why Ns do not add up to group N). Open table in a new tab HPF: high Power Field; IQR: inter-Quartile Range. p-values derived from Fisher's exact test or Kruskal Wallis test, as appropriate. Staining was not obtained for all slides for all markers (that is why Ns do not add up to group N).