Nonspecific immunotherapy Innate Immune system and cytokine

Nature kill cells are the central component of the innate immunity and play an important role in cancer immunosurveilance. It has been reported that NK cells can recognize and control tumor growth by direct cellular cytotoxicity and secrete immunostimulatory cytokines such as IFN-y. The further researches have demonstrated NK cells can eliminate tumor cell by inhibiting cellular proliferation, angiogenesis, promoting apoptosis and stimulate the adaptive immune system. In mouse experimental models, NK cell-mediated elimination of tumor cells induced the subsequent development of tumor-specific T cell responses to the parental tumor cells as a bridge between innate and adaptive immune responses(48).

In 1984, K. Funa has found patients with pancreatic adenocarcinomas expressing deficiencies in the NK-IFN system at least three levels: (1)diminished basal NK activities, (2)decreased sensitivity of NK to IFN in virto, (3)decreased atypical IFN production by staphylococcus aureus cowan I (SACoI)(49).

In a recent clinical trial, a patient exhibited regression of several pancreatic cancer metastases following the administration of the immune modulator Ipilimumab (anti-CTLA-4 antibody). Tumor infiltrating lymphocytes (TIL-2742) and an autologous tumor line (TC-2742) were expanded from a regressing metastatic lesion excised from this patient. Natural killer (NK) cells predominated in the TIL (92% CD56(+)) with few T cells (12% CD3(+)). A majority (88%) of the NK cells were CD56(bright)CD16(-). TIL-2742 secreted IFN-y and GM-CSF following co-culture with TC-2742 and major histocompatibility complex mismatched pancreatic tumor lines. After sorting TIL-2742, the purified CD56(+)CD16(-)CD3(-) subset showed reactivity similar to TIL-2742 while the CD56(-)CD16(-)CD3(+) cells exhibited no tumor recognition. In co-culture assays, TIL-2742 and the NK subset expressed high reactivity to several pancreatic cancer cell lines and could lyse the autologous tumor as well as pancreas cancer lines. Reactivity was partially abrogated by blockade of TRAIL. This represents the first report of CD56(+)CD16(-) NK cells with apparent specificity for pancreatic cancer cell lines and associated with tumor regression following the treatment with an immune modulating agent(50).

Clinical and experimental evidence demonstrate the extent of NK cell activity in peripheral blood is associated with cancer risk in adults(51). In recent years, novel studies have discovered the phenotypic status and functionality of NK cells in tumor site and also in peripheral blood of cancer patients. Research has shown that only a few infiltrating NK cells which are unlikely to greatly contribute to eliminate the tumoe cells(52). Due to NK's inefficient homing into malignant tissues, the situation may be overcome by cytokine-mediated activation in immunotherapeutical regiment53). However, novel studies of tumor-associated NK cells demonstrated a striking phenotype, supporting the notion that tumor-induced alterations of activating NK cell receptor expression may hamper immune surveillance and promote tumor progression.

Bhat R reported the finding:besides its intrinsic oncolytic activity, parvovirus H-1PV is able to enhance NK cell-mediated killing of pancreatic adenocarcinoma cells. The experiment show that H-1PV infection of Panc-1 cells increases NK cell capacity to release IFN-y, TNF-a and MIP-1a/ p. Multiple activating receptors are involved in the NK cell-mediated killing of Panc-1 cells. Indeed, blocking of the natural cytotoxicity receptors-NKp30, 44 and 46 in combination, and NKG2D and DNAM1 alone inhibit the killing of Panc-1 cells. Interestingly, H-1PV infection of Panc-1 cells overcomes the part of inhibitory effects suggesting that parvovirus may induce additional NK cell ligands on Panc-1 cells. The enhanced sensitivity of H-1PV-infected pancreatic adenocarcinoma cells to NK cell-dependent killing could be traced back to the upregulation of the DNAM-1 ligand, CD155 and to the downregulation of MHC class I expression. The data suggests that NK cells display antitumor potential against PDAC and that H-1PV-based oncolytic immunotherapy could further boost NK cell-mediated immune responses and help to develop a combinatorial therapeutic approach against pancreatic cancer(54).

NK cells can eliminate tumor cells through their ability to mediate antibody-dependent cellular cytotoxicity(ADCC). Nk cell recognition of an antibody-coated target cell results in rapid NK cell activation and degranulation(55). NK-cell mediated ADCC play a part in mechanisms of tumor-targeted mAbs which targeting CD20, Her2/neu, epidermal growth factor receptor(EGFR)(56)(57). Because HLA class I is a ligand for inhibitory receptor family, killer cell immunoglobulin-like receptor of NK cells(58), loss of HLA class I expression can lead to escape of antigen-dependent cytotoxicity of CD8+ CTL and increase the possibility as a target of NK cell cytotoxicity. In pancreatic cancer, total HLA class I loss is 6% in primary versus 43% in metastastic tumors;0 in G1, 33% in G2 and 67% in G3(59).

In research of nonspecific immunotherapy, many cytokines were used to elevate the ability of the immune system. it is possible to activate tumor-specific antitumor immune responses by systemic injection of cytokine or introduction of cytokine gene into tumors through activating natural killer(NK) cells and tumor-specific CD4+ T cells and cytotoxic T lymphocytes(CTL). Different cytokines may stimulate antitumor immune responses by different mechanisms.

Granulocyte Marcophage Colony-Stimulating Factor(GM-CSF) and IL-2 are the most popular cytokines used in cancer immunotherapy. GM-CSF, which can stimulate bone marrows differentiating and maturing to neutrophils, monocytes and dendritic cells, is used to generate cancer immunotherapy called GAVX(60). In clinical trials using the GAVX, induction of systemic antitumor immune response and clinical activity was observed in pancreatic cancer, melanoma, and renal cell carcinoma. In a study of combination of chemotherapy and immunotherapy, two GM-CSF secreting pancreas cancer cell lines (CG8020/CG2505) as immunotherapy were administered alone or in sequence with Cy in patients with advanced pancreatic cancer. Results showed GM-CSF secreting pancreas cancer cell lines demonstrated minimal treatment-related toxicity in patients with advanced pancreatic cancer. Also, mesothelin specific T cell responses are detected/enhanced in some patients treated with CG8020/CG2505 immunotherapy. In addition, Cy modulated immunotherapy resulted in median survival in a Gemzar resistant population similar to chemotherapy alone(61).

Interlukin-2 (IL-2) is a growth factor that stimulates innate immunity cells. Different dose of IL-2 has been proved either enhance or decrease cellular and humoral immune functions. Rosenberg used it developing lymphokine-activated killer(LAK) therapy for cancer(62). In a randomized study, preoperative subcutaneously IL-2 immunotherapy at 12 million IU for 3 consecutive days before surgery is able to abrogate the effects of the surgical trauma and recover a normal immunofunction in pancreatic cancer patients(63). Recombinant interleukin-2 (rIL-2) was used in a study which aimed to evaluate the toxicity of pre- and postoperative rIL-2 treatment and the effects on innate immunity both in peripheral blood and in cancer tissue of patients with resectable pancreatic adenocarcinoma. Seventeen patients received high dose rIL-2 preoperative subcutaneous administration and two low dose postoperative cycles. NK cell and eosinophil count were evaluated in blood and in pancreatic surgical specimens. The result showed toxicity was moderate. In the early postoperative period, blood NK cells and eosinophils significantly increased compared to basal values (p < 0.02). Preoperative high dose rIL-2 administration is able to counteract surgery-induced deficiency of NK cells and eosinophils in peripheral blood in the early postoperative period, although it cannot overcome local mechanisms of immune tumor escape in cancer tissue. The amplification of innate immunity, induced by immunotherapy, may improve the control of metastatic cells spreading in the perioperative period(64).

As a bridge between innate and adaptive immune response(65), IL-12 is independently identified as natural killer-stimulating factor (NKSF) and cytotoxic lymphocyte maturation factor(66), which induces proliferation of NK and T1 cells and production of cytokines, especially IFN-y ' and also enhances the generation and activity of CTLs, through activation of STAT4(67).

The combination of IL-12 and IL-27 can modify the polarization of Th2 effectors by both reduction of IL-5, GM-CSF and IL-13 and induction of IFN-gamma production, which lasted after cytokine removal. Besides, the combined treatment functionally modulated the Th2 polarization of CEA-specific CD4(+) T cells and enhanced pre-existing Th1 type immunity(68).

In recent study, IL-12 was coformulated with the biodegradable polysaccharide chitosan which could enhance the antitumor activity of IL-12 while limiting its systemic toxicity. Antitumor efficacy of IL-12 alone and IL-12 coformulated with chitosan (chitosan/IL-12) was assessed in mice bearing established pancreatic (Panc02) tumors. Additional studies involving depletion of immune cell subsets, tumor rechallenge, and CTL activity were designed to elucidate mechanisms of regression and tumor-specific immunity. Coformulation with chitosan increased local IL-12 retention from 1 to 2 days to 5 to 6 days. Weekly i. t. injections of IL-12 alone eradicated <10% of established Panc02 tumors, while i. t. chitosan/IL-12 immunotherapy caused complete tumor regression in 80% to 100% of mice. Depletion of CD4(+) or Gr-1(+) cells had no impact on chitosan/IL-12-mediated tumor regression. However, CD8(+) or NK cell depletion completely abrogated antitumor activity. I. t. chitosan/IL-12 immunotherapy generated systemic tumor-specific immunity, as >80%

of mice cured with i. t. chitosan/IL-12 immunotherapy were at least partially protected from tumor rechallenge. Furthermore, CTLs from spleens of cured mice lysed MC32a and gp70 peptide-loaded targets. The reasearch has demonstrated Chitosan/IL-12 immunotherapy increased local retention of IL-12 in the tumor microenvironment, eradicated established, aggressive murine tumors, and generated systemic tumor-specific protective immunity(69).

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