Potential immune priming of the tumor microenvironment with FOLFOX chemotherapy in locally advanced rectal cancer

Abstract

Strategies to enhance tumor immunogenicity may expand the role of immunotherapy beyond the mismatch repair-deficient subtype. In this pilot study, biopsies were performed at baseline and after four cycles of FOLFOX in eight patients receiving neoadjuvant chemotherapy for stage II/III locally advanced rectal cancer. Immunostaining was performed for T cell subsets (CD3+, CD8+, CD45RO+); macrophages (CD163+); T regulatory cells (FOXP3+); and expression of MHC class I, PD-1 and PD-L1. Changes in cell number or intensity were quantified and correlated with treatment response. Pretreatment patterns of immune infiltrates were mixed and did not correlate with treatment response. Posttreatment increases in T cell infiltrates (CD3+, CD8+ and CD45RO+) and MHC-I expression were observed in five patients. CD163+ cell numbers increased in four patients. FOXP3+ cell numbers increased in two patients, decreased in two other patients and remained unchanged in three patients. PD-1 scores increased in seven patients, and PD-L1 scores increased in four patients. Changes in tumor T cell responses did not correlate with treatment response. Changes in FOXP3+ cells were associated with treatment response in some patients: two patients with increases in FOXP3+ cells had poor responses, whereas the patient with the greatest reduction in FOXP3+ cells had a complete response. The patient with a complete clinical response had a much higher increase in MHC-I expression than other patients. These results suggest that chemotherapy can increase immune activity in the tumor microenvironment and could potentially be utilized to prime immune responses prior to immunomodulatory treatments.

Drug-Drug Interactions of Irinotecan, 5-Fluorouracil, Folinic Acid and Oxaliplatin and Its Activity in Colorectal Carcinoma Treatment

“…This paves the way to potential new therapies to replace or combine with the current standard of care. A combination of FOLFOXIRI with immunotherapy may revolutionize standard clinical care [70][71][72]. The presence of immune cells in the tumor microenvironment of mCRC after first-line chemotherapy treatment can be used to predict potential combinations with immunotherapy [72][73][74].…”

“…A combination of FOLFOXIRI with immunotherapy may revolutionize standard clinical care [70][71][72]. The presence of immune cells in the tumor microenvironment of mCRC after first-line chemotherapy treatment can be used to predict potential combinations with immunotherapy [72][73][74]. FOLFOX or FOLFOXIRI treatment triggers immune cell infiltration [74], increases the expression of immune-modulatory receptors and can prime and enhance for some time the immune cell activity at the tumor site [72,74].…”

“…The presence of immune cells in the tumor microenvironment of mCRC after first-line chemotherapy treatment can be used to predict potential combinations with immunotherapy [72][73][74]. FOLFOX or FOLFOXIRI treatment triggers immune cell infiltration [74], increases the expression of immune-modulatory receptors and can prime and enhance for some time the immune cell activity at the tumor site [72,74]. Interestingly, it has been demonstrated that FOLFOX treatment upregulates the expression of PD-L1 on cancer cells, inducing immune resistance.…”

Two nanoformulations induce reactive oxygen species and immunogenetic cell death for synergistic chemo-immunotherapy eradicating colorectal cancer and hepatocellular carcinoma

“…FOLFOX has been long utilized as the standard chemotherapy for CRC and HCC patients at advanced stages [ 1 , 2 ]. It also demonstrates great potential for induction of robust antigen release from dying tumor cells and for generation of effector and memory T cells [ 55 , 56 ]. In this study, two AEAA-targeted PEGylated nanoformulations namely Nano-FdUMP (fig.…”

Immunotherapy for the treatment of colorectal cancer

“…The current standard of care for mCRC is combination chemotherapy with a fluoropyrimidine (5-fluorouracil, 5-FU) and a platinum-based agent, oxaliplatin (FOLFOX) or the topoisomerase inhibitor irinotecan (FOLFIRI). While the mechanism of these regimens was previously thought to be purely cytotoxic, recent evidence has identified the crucial role of the immune system in both chemotherapy-mediated cytotoxicity 16,17 and underlying CRC pathogenesis. 18,19 The rationale for using ICI in CRC stems from the understanding that tumors can co-opt self-tolerance mechanisms that suppress T cell activation through upregulation of immune checkpoints, and that antibodies targeting several of these checkpoints, including cytotoxic T-lymphocyte-associated antigen (CTLA-4) and programmed cell death protein 1 (PD1), will augment T cell response to tumor antigens.…”