Effect of Pemetrexed on Innate Immune Killer Cells and Adaptive Immune T Cells in Subjects With Adenocarcinoma of the Pancreas

Abstract

Baseline levels of innate and adaptive immune cell functions were studied in patients with pancreatic cancer. The effects of pemetrexed were measured at 7 and 14 days after initial therapy then 14 days after combination therapy with gemcitabine. Pretherapy levels of absolute numbers of natural killer (NK) cells positively correlated with survival. Cytolytic units of NK activity correlated positively with NK cell numbers. Pemetrexed decreased NK cytolytic units to significance when combined with gemcitabine. Pemetrexed increased intracellular accumulation of interferon gamma (IFNγ) in NK cells that correlated negatively with survival. Addition of gemcitabine decreased IFNγ-producing NK cells to baseline. Memory (CD45RO*) T cells enumerated at baseline correlated negatively with survival but were decreased by pemetrexed therapy. Memory T cells were increased in subjects with greater B7-H3 expression in tumor tissue, whereas OX40*-activated total T cells and helper T-cell subset were decreased. FoxP3*, CD8* T cells correlated positively with progression-free interval and survival. In conclusion, innate NK-cell immunity and FoxP3*, CD8* T cells seemed beneficial to pancreatic cancer patients. Higher levels of B7-H3 expression in pancreatic tumors were detrimental to effective immunity. Although pemetrexed therapy increased activation of a subset of NK cells to produce IFNγ, addition of gemcitabine abated those responses, decreasing IFNγ-producing NK cells, whereas NK cells producing interleukin-2 without IFNγ at this timepoint positively correlated with survival. Innate immunity and adaptive immunity thus are important in defense against pancreatic cancer. Progression-free interval and survival were longer than observed in a phase III trial where gemcitabine preceded pemetrexed suggesting that a larger trial of pemetrexed preceding gemcitabine is warranted.

Effect of Surgery on Pancreatic Tumor-Dependent Lymphocyte Asset

“…The direct correlation between NK cell number and cytotoxic function has been already noted by Davis et al 43 in pancreatic cancer patients and could derive from an alteration in NK cell proliferation and function, probably due to the profound tumor-dependent (at presurgery) and surgery-dependent (at 7 days postintervention) modulation of soluble factors. Indeed, the well-known deregulation of NK cell–modulating cytokines, such as IL-2, IL-12, and IL-18, and of CD4/CD25 regulatory T-cell subset in pancreatic cancer patients could set up an altered microenvironment, in which NK cells adopted aberrant proliferation, differentiation, and functional behavior.…”

“…19 Natural killer cells may exert their protective role by killing pancreatic cancer cells, which have lost major histocompatibility complex class I expression 42 and/or express-induced ligands for NKG2D activating receptor, 38 and their increased cell number may represent an important defense against residual cancer cells; actually, a positive correlation between pancreatic cancer patient survival and their PB NK cell absolute count has been previously described. 43 …”

Role of immune cells in pancreatic cancer from bench to clinical application

“…[73] The numbers of circulating NK cells are reduced in patients with advanced PC [29] , and pretreatment levels of peripheral NK cells positively correlate with survival in patients with PC. [32] These findings indicate that NK cells exert some control over tumor progression. Based on histologic evaluation, Ene-Obong et al [8] recently demonstrated reduction in numbers of NK cells and CD8 + T cells in the juxta-tumoral area as compared with the pan-stromal area of human PC, potentially due to sequestration and preferential migration to activated pancreatic satellite cells.…”

Clinical Efficacy of Bevacizumab Concomitant with Pemetrexed in Patients with Advanced Non-small Cell Lung Cancer

“…In recent years, studies showed that pemetrexed could be used and had certain effects on a variety of commonly seen tumors like lung cancer, colorectal cancer, breast cancer and pancreatic cancer, etc.. (Gerber et al, 2013;Zhang et al, 2013;Deng et al, 2013;Davis et al, 2012). National Comprehensive Cancer Network (NCCN) guidelines (2009) recommended that after first-line treatment of platinum-containing regimen or monotherapy, NSCLC patients with SD were considered to be effective after 4~6 cycles of pemetrexed chemotherapy, who could continue the original chemotherapy or added with maintenance therapy until disease progression.…”