Dhaka 23rd October, 2015. Hats off to Dr. Shamsul Alam, at the Laboratory of Cell Immune Biology, Bethedsa, Maryland for his outstanding contribution which will pave the way to the cure of pancreatic cancer. The entire community of GNOBB members join hands in paying a glowing tribute to Dr. Alam. Although Dr. Alam’s finding is in mice, it is definitely a step forward toward discovering the drug for the cure of this deadly human cancer.Immune system is poised to provide protection from infection to pathogens. T cells play central role in orchestrating immune responses by bridging the response of Antigen presenting cells and building long lasting memory to the antigen. However, persistent activation of T cells leads to serious autoimmune diseases like multiple sclerosis, psoriasis, rheumatoid arthritis, and cancer etc.

The mitogen activated protein kinase (MAPK) p38 has a critical role in proinflammatory responses. Like all MAPKs, p38 is activated by a cascade, in which upstream MAPK kinases (MAPKKs) phosphorylate p38 on Thr 180 and Tyr 182 of the activation loop (the classic pathway). Unlike all cells of the body, T cell possesses a unique mode of p38 activation downstream of the T-cell receptor (TCR). TCR ligation activates a protein tyrosine kinase called Zap70, which phosphorylates p38 on Tyr-323, leading to automonophosphorylation of Thr 180 (the alternative pathway) (1). Studies were initially designed to investigate the novel T cell-specific mechanism of p38 activation, asking why in evolution T cells acquired such a unique pathway and how it controls inflammatory responses. We found that the p38 alternative pathway controls the upregulation of NFATc1 (also named NFAT2, Nuclear Factor for activated T cells type 2) and its downstream transcriptional regulator IRF4 (interferon regulatory factor 4), the two key factors that control the production of inflammatory cytokines such as TNF-α, IFN-γ, and IL-17A. Moreover, TCR-mediated NFATc1 activation by p38 is countered by stress-induced activation of p38, a phenomenon that we showed is the underlying molecular mechanism for the effectiveness of UV treatment in human psoriasis. This study has been published in the Journal of Experimental Medicine (2).

We have further interested in inflammatory cancer in particular pancreatic cancer by asking what role T cell p38 alternative pathway might play. We observed that in human pancreatic ductal adenocarcinoma (PDAC) a high percentage of infiltrating p38+pY323+ T cells was associated with large numbers of TNF-α and IL-17A-producing CD4+ tumor-infiltrating lymphocytes (TIL) and associated with shorter survival.

We have generated mice by replacing endogenous p38α and p38β with mutants with a Tyr to Phe substitution (double knock-in [DKI] mice) at residue 323 hence they can’t activate the alternative pathway leaving the classical activation pathway intact. Tumor growth was drastically reduced in subcutaneously grafted pancreatic cancer cell line (Panc02) in DKI mice than Wild type (WT). Moreover, adoptive transfer of the bone marrow of DKI mice showed longer survival of KPC mice (p53 mutant and Kras expressing mice, which spontaneously develop pancreatic cancer and mimics human PDAC) compared to that of (WT) mice. Therefore, we became interested to target the p38 alternative pathway.

Gadd45α is a physiologic constitutive inhibitor of the alternative pathway, and Gadd45α knock out mice spontaneously develop autoimmune vasculitis because of the chronic activation of the p38 alternative pathway (3). Conversely, inactivation of the alternative pathway prevents autoimmunity in Gadd45α knock out mice (Jirmanova et al., 2011. Blood). Thus, we took advantage of the physiologic inhibitor to target the p38 alternative pathway. The shortest fragment of Gadd45α has been mapped which was found to be the central 71-85 amino acid residue. The peptide was fused with 11 Arginines to make cell membrane permeable and hence termed as (11R) 71-85. The cell-permeable peptide specifically acts on T cells, inhibits inflammatory cytokine production like TNF-α and IL-17A from tumor infiltrating CD4+ T cells by targeting the p38 alternative pathway, which ultimately inhibits pancreatic cancer progression in both subcutaneously grafted Panc02 and KPC mouse models. Because of the efficacy of this novel therapy observed in our preclinical studies, the peptide has been patented from National Cancer Institute. The manuscript describing the effect and relevance of this drug has recently been accepted for publication in Nature Medicine (4). Thus, TCR-mediated activation of tumor-infiltrating CD4+ T cells results in alternative p38 pathway mediated production of pro-tumorigenic inflammatory factors, and can be targeted for therapeutic benefit. [The summary was kindly provided by the author, Dr Shamsul Alam himself.]