**5. Immunonutrition**

The postoperative immune response is multifactorial with the release of inflammatory Th1 cytokines, such as IL-6 and TNF-a, and corticosteroids immediately after cancer surgery. Subsequently, even after 2 h from the surgical procedure, there is a reduction of the Th1 cytokines, while the Th2 cytokines, such as TGF-b, and IL-10 rise rapidly increasing the accumulation of immunosuppressive myeloid-derived suppressor cells, and immuneinhibitory cytokines [84]. This shift toward the Th2 immune response deregulates the cellular immunity, enhancing susceptibility of the cancer patient to infection, sepsis, and MOF [85– 87]. Furthermore, there is a quantitative reduction of T lymphocytes, which depends on the volume of blood loss during surgery. Also, there is a reduction in the number of white blood cells (WBCs) called leucopenia, which causes immunosuppression that combined with reduced cytokine secretion and suppression of T-lymphocyte responses, and reduced levels of macrophages may cause postoperative sepsis that may lead to morbidity. However, sepsis may be inhibited by postoperative release of anti-inflammatory cytokines, prostaglandins, and nitric oxide, which requires arginine as a substrate for its production by nitric oxide synthase [88]. Since plasma levels of arginine are reduced in septic patients, we need to establish a positive nitrogen balance by supplementation of arginine as an immunonutrition approach. This amino acid regulates blood flow by producing nitric oxide (NO), and it functions as an immunomodulator by enhancing the antitumor cytotoxicity of neutrophils and macrophages [89–92]. Furthermore, the proper antitumor function of T cells requires arginine. The tumor microenvironment contains nitric oxide synthase (NOS) and arginase I, which are upregulated by tumor-induced MDSC, acting as an immunosuppressive mechanism that leads to a deficiency of arginine, which subsequently suppresses the antigen-specific T-cell responses by downregulating the T-cell receptor [93,94]. Within a few hours after cancer surgery, there is an evident reduction of arginine in the circulation of the cancer patient [95,96] because arginine is metabolized by arginase-I, which may be downregulated by omega-3 fatty acids that are metabolized to PGE3, inhibiting production of immunosuppressive Th2 cytokine, and increasing the production of protectins and resolvins, which promote tissue repair [97]. Immunonutrition in the surgical cancer patient with arginine may improve trauma healing, enhance macrophage function, and lymphocyte immune responses enhancing resistance to infection at the postoperative stage [98]. A functional immune system is required for protecting the surgical cancer patient from the high risk of postoperative infections, which can be achieved by perioperative immunomodulating formulations that can circumvent postoperative immunoparesis and prevent sepsis by activating the immune cell responses, and modulating

Other protective perioperative practices include minimally invasive surgical procedures, circumvention of immunosuppressive drugs, and reduction of blood transfusions [99]. Radical surgery combined with old-age neuroendocrine response and administration of analgesics may suppress the activity of the innate immunity and specifically NK cells, which leads to tumor progression since tumor cells circumvent tumor immunosurveillance and subsequent cytolysis [100–104]. In addition, operative anesthetics, such as halothane, thiopental, and ketamine, may suppress even further the activity of NK cells promoting metastasis. Thus, immunonutrition may stimulate the immunity, while other factors such as hypothermia,

alcohol, and mainly stress may enhance tumor progression [105].

inflammation.

28 Immunopathology and Immunomodulation

It is very important that more than one third of all cancer deaths are related to nutritional complications, which have been caused by side effects of the major treatments for cancer even the targeted ones. With the administration of nutritional therapy, we can reduce or even inhibit the nutritional complications of cancer, improving nutritional status and healing, maintain normal weight by preventing muscle wasting, and mainly reduce side effects and mortality or morbidity by enhancing the overall effectiveness of anticancer treatments and their combinations while we may preserve and even enhance quality of life. Furthermore, with immunonutrition, we may boost the immune system of cancer patients, especially those who are hospitalized and malnourished. The immune system of cancer patients can be modulated with immunonutritional formulations, which may contain immunostimulant and antiinflammatory nutrients such as protein, carbohydrate, amino acids, lipids, mineral, trace elements, and vitamins including glutamine, which may enhance immune cell activity, improve nutritional status, and reduce hospitalization time reducing risk of infections. Other nutraceuticals include arginine, which boosts immune function, prevents infection, and repairs tissue after surgery; omega-3 fatty acids, which have anti-inflammatory properties minimizing the risk for cancer cachexia; ribonucleic acid (RNA), which may stimulate immune cell division and activity; taurine, which reduces inflammation; vitamin C or ascorbic acid, which supports immune function and promotes wound healing; selenium, which supports immune function preventing infection; turmeric, which has anti-inflammatory effects especially at the postoperative stage; vitamins B12, B6, and B1, which may prevent post-operative immunosup‐ pression; zinc, which is important for normal immune system function; and wound healing after surgery [111]. Also, natural products of alternative medicines, such as botanical or herbal plant derivatives, and mind–body practices under an integrative medicine approach may enhance the anticancer effects of conventional anticancer treatments, reducing their systemic toxicity; alleviate clinical symptoms including pain, which are induced by cancer; and prolong survival rates of cancer patients mainly by enhancing tumor immune responses via overex‐ pression of classic MHC molecules, induction of apoptosis in tumor cells via the Fas/FasL pathway, and elimination of oncogenic cancer stem cells by inhibiting tumor immunoresist‐ ance [112–115]. Further, alternative medicine therapeutic strategies may reverse the tumorinduced immunosuppressive phenotype regulating the antitumor properties of the immune cells of the cancer patients by enhancing the antitumor abilities of T lymphocytes, regulating the M1/M2 phenotypes of tumor-associated macrophages (TAM), eliminating myeloidderived suppressor cells (MDSC), enhancing antigen-presenting capacity of dendritic cells (DCs), and regulating the secretion of Th1/Th2 immune factors.

Generally, by using an integrative medicine immunotherapeutic approach where alternative medicine practice which follows a multitargeted and bidirectional regulation may compensate for deficiencies of conventional orthodox western medicine, which is characterized by specificity, we may achieve a synergistic effect concerning circumvention of tumor-induced immunosuppression and enhancement of antitumor immunomodulation followed by minimization or elimination of side effects prolonging the survival rate of advanced stage and metastatic cancer patients promoting their quality of life [116–121].

#### **6. Conclusion**

The key is to treat each cancer patient under a precision or personalized evidence-based medicine approach, which must rely on clinomics, including transcriptomics, genomics, immunomics, lipidomics, glycomics, proteomics, metabolomics, nutrigenomics, and mainly epigenomics, whose alterations in their noncoding RNA genes are reversible especially with immunonutrition. The precise immunotherapeutic approach against cancer may act synerg‐ istically with conventional anticancer therapies, such as surgery, chemotherapy, and radio‐ therapy combined with therapies based on molecular targeting, which are tailored for each patient on a pharmacogenomic basis. Also, they can be combined with nanomedicine for specific molecular targeting and circumvention of biological milieu interactions, which may tremendously enhance therapeutic efficacy with simultaneous reduction of systemic toxicity.
