Review Article ISSN: 2056-4546 Integrative Cancer Science and Terapeutics Integr Cancer Sci Terap, 2016 doi: 10.15761/ICST.1000189 Volume 3(3): 465-472 Macrophages directed approaches are paramount for efective cancer immunotherapies Vinod Nadella 1 , Sandhya Singh 2 and Hridayesh Prakash 1 * 1 Translational Medicine laboratory, School of Life sciences, University of Hyderabad, Telangana, India 2 Department of Animal Biology, School of Life Sciences, University of Hyderabad, Telangana, India Abstract Macrophages are double edge sword component of immunity and display phenotypical and functional plasticity which enable them to both promote and eliminate established tumors. Under the infuence of immunosuppressive tumor microenvironment, tumor infltrating iNOS+ and CD11b+ M-1 regulatory macrophages get polarized to Tumor associated macrophages (TAM) which are Ym-1 and Arginase+ iNOS- (M-2) and tropic to variety of tumors. Increased density of TAM in the variety of tumors has been correlated with poor prognosis which is due to their infuence on angiogenesis and tissue re-modelling by which TAM support tumorigenesis as well metastasis. Apart from this, TAMs are also responsible for the maintenance of tumor microenvironment by their virtue of inducing endothelium anergy, which actually represent physical barrier for majority of cancer directed immune / chemotherapies. Terefore functional retuning of TAM to an M-1 phenotype is paramount for efective immunotherapy against established tumors which could be aforded by total body gamma irradiation in neoadjuvant settings or adoptive transfer of iNOS+ macrophages. In this review, we will discuss both existing as well future cancer directed immuno / adjuvant therapies targetting immunosuppresive tumor microenviorment particularly tumor-associated macrophages (TAM) for enhancing immunty against solid tumors (adenocarcinoma). Introduction Afer infections, cancer is next major cause of global morbidity and mortality and poses a signifcant thread on both patients and their families and the healthcare system as a whole. Available data indicate that the number of cancer-related deaths is more than those caused by AIDS, malaria, and tuberculosis combined; about one in four deaths is due to cancer. A major reason for this high mortality rate lies in resistant nature of variety of tumors against anti-cancer agents and bystander toxicity on healthy tissues and organs [1-4]. Cancer is caused by complex processes, which are directly linked to ‘cell division’, the fundamental process of life. Unlike normal cells that follow an orderly path of growth, division, and death, cancer cells continue to grow and divide continuously leading to aberrant cell mass which survive programmed death called ‘Apoptosis’. According to their origin and location [5] cancers are classifed into 200 types with varying degree of resistant against existing anti-cancer drug / therapies. Among various reasons, inefcient T cell migration is a major limitation [6] of cancer immunotherapy in general. Despite enough advancement was made in this feld, none of the therapeutic intervention could prolong the survival of tumor patients beyond few weeks. Tis is mainly due to symbiotic association of tumor cells and tumor infltrating macrophages (TAM) which drives sterile infammatory response during the course of tumorigenesis. Various angiogenesis factors get accumulated at tumor site or within tumor microenvironment which serve as prognostic factors for cancer progression and renders tumor endothelium impermissive for immune cells infltration. Tough, many treatment options have been suggested / made over the past several decades, until today, no single treatment option is promising in controlling solid tumors like pancreatic and lung cancers. Classical/Traditional treatment options Depending on cancer type, tumor size and vasculature, so far three basic and fundamental approaches have been employed for cancer directed therapy and these are surgical resection of tumor, chemotherapy and radiotherapy. As relying on surgery is limited to early stage tumours, treatment options such as chemotherapy and radiotherapy are geared towards killing the cancer cells [7-10] themselves and are currently in use to date. However, these procedures are non-selective and have considerable clinical side efects. Te hypoxic or anoxic micro-environment of solid tumour like adenocarcinoma poses a challenge to traditional cancer treatment [11-13] mainly due to increased angiogenesis of tumor. Tis predisposes tumour cells less susceptible to death by various chemotherapeutic drugs and / or radiotherapy which aimed to increased intratumoral oxygenation for killing by induction of apoptosis. Tus these do not represent good therapeutic options for the treatment of solid tumors cancer. Alternative/Advanced treatment options In recent years, various signalling pathways, which are important / decisive for tumor metabolism and growth, have been targeted by using pharmacological inhibitors for controlling the tumor growth [14]. Many genes like EGFR, p53, TRP53, PTEN, PI-3K XIAP, NF-kb and STAT3 have been identifed and targeted [15-17] both chemically / genetically for controlling for rendering tumor cells sensitive for apoptosis. Tough, in line with these, various anti-tumor agents and Correspondence to: Dr. Hridayesh Prakash , Translational Medicine Laboratory, School of Life Sciences, University of Hyderabad, P.O. Central University, Hyderabad 500 046, Telangana, India, Tel: +91-40-66794704, Fax: +91-40- 23010307/23010120, E-mail: hridayesh.prakash@gmail.com Key words: macrophages, tumor microenvironment, nanoparticles, radiotherapy, immunotherapy, adenocarcinoma, pancreas Received: April 05 2016; Accepted: May 02, 2016; Published: May 05, 2016