ImmunotherapyVol. 4, No. 2 EditorialFree AccessImmune system plays an important role in the success and failure of conventional cancer therapyMichael J Gough & Marka R CrittendenMichael J Gough* Author for correspondenceEarle A Chiles Research Institute, Robert W Franz Cancer Research Center, Providence Cancer Center, Portland, OR 97213, USA. Search for more papers by this authorEmail the corresponding author at michael.gough@providence.org & Marka R CrittendenThe Oregon Clinic, Portland, OR 97213, USASearch for more papers by this authorPublished Online:17 Feb 2012https://doi.org/10.2217/imt.11.157AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit There are a multitude of different drugs available to kill cancer cells. While there has been an iterative improvement in the development of models to test drugs, there is a limited correlation between preclinical success and clinical success [1]. Preclinical studies of new drugs focus on cell lines and xenografted human tumors in immunodeficient mice and, thus, ignore the contribution of the immune system. The field of cancer drug development has moved towards targeted inhibitors that focus on key signal transduction pathway molecules such as Erk and Akt, which are important in cancer cell survival. It is of concern to immunologists that these are also critically important regulators of immune cells.The majority of solid tumors grow in immune-competent patients. A critical stage in the evolution of a tumor to the point where it presents as a symptomatic mass requires the control of host-immune responses. CD8 T cells specific for tumor antigens are identifiable in patients with many types of cancer, indicating that the immune system is capable of recognizing tumors. Tumors arise more readily in immunodeficient animals, but are less equipped to resist adaptive immune control [2]. This implies that, at presentation, advanced cancers in otherwise normal patients have some degree of control over their local immune environment. Nonetheless, current treatment decisions are not influenced by the presence or absence of an antitumor immune response.While cancers can systemically perturb immune systems, the majority of patients sustain the ability to clear opportunistic infections and show few functional signs of systemic adaptive immune deficiency, such that even multiple-treated, late-stage cancer patients can be vaccinated. Instead it appears that tumors have a predominately locoregional effect on the immune system with increasing systemic effect with progressive tumor burden. Tumor macrophages appear to be critical in regulating this local immune environment in cancer, and this has consequences for patients. Tumors that present with a high-macrophage infiltrate, with a poor T-cell infiltrate, or with a high macrophage:CD8 ratio have a poorer prognosis [3–5]. While the importance of the immune system to cancer therapy is not a difficult sell to immunologists, chemotherapy, surgery and radiation therapy are commonly considered immunosuppressive interventions. However, amongst patients receiving these treatments, the local immune environment matters. Cancer patients with an impaired immune response develop metastases faster following surgery, radiation and chemotherapy [6]. In a murine model, depletion of CD8 T cells increased local recurrence following surgery [7]; by contrast, stimulating the endogenous immune response at the time of the operation has been shown to decrease local recurrence [7,8]. Similarly, in animal models, the efficacy of radiation therapy is partly dependent on functional T-cell responses [7,9], and radiation therapy can be made more effective by improving T-cell immune responses [7,9,10]. Thus, the local immune environment within a tumor may play a critical role in the success or failure of conventional therapies and should be considered when designing and developing new therapies. We propose that the stromal environment of the tumor can protect those small numbers of cells that escape cytotoxic and surgical therapies. This stromal environment is dictated by the polarized myeloid cells in the tumor, and in turn myeloid polarization is influenced by adaptive immune cells. Since the sum total of the tumor immune environment is influential, the unseen contribution of endogenous immunity should be considered when testing therapies in preclinical models.Multiple layers of evidence exist regarding the role of the endogenous immune system in tumorigenesis, tumor progression and tumor resistance to therapy. Spontaneous and chemically-induced tumors, which may accurately model the progressive stages of carcinogenesis, are highly influenced by the host immune system. Chemically-induced tumors require chronic proinflammatory conditions, including expression of the proinflammatory cytokine TNF-α for carcinogenesis [11]. By contrast, progression to invasive cancer and metastatic spread is independent of TNF-α [11], but is dependent on macrophage production of the inflammatory resolution-phase cytokine VEGF [12]. Elevated VEGF expression is associated with the emergence of the characteristic vascular loops and sprouts of angiogenic neovasculature in developing tumors, and results in an elevated interstitial pressure compared with normal tissues [13]. This elevated interstitial pressure results in poor drug perfusion, despite leaky vasculature, and is one of the factors contributing to the many log-fold difference in efficacy of chemotherapy in vitro and in vivo[14]. VEGF inhibition results in decreased interstitial pressure concomitant with fewer immature vessels or ‘vascular normalization’ [15]. Therefore an important advantage of targeting VEGF may be in better chemotherapy perfusion into the tumor. Olive et al. demonstrated that targeting the tumor stroma with inhibitors of hedgehog signaling resulted in vascular remodeling, increased drug penetration and increased the efficacy of chemotherapy in murine models [16]. These data demonstrate that the tumor stroma actively protects cancer cells from conventional therapy, and we propose that the development of a negative tumor stroma is directed by immune infiltrates into the tumor site.There are good data implicating tumor macrophages in dictating the stromal environment of the tumor. Macrophage activation may be broadly split into classical (M1) activation, associated with proinflammatory responses, versus alternative (M2) activation, associated with inflammatory resolution and wound healing. Tumors have famously been described as ‘wounds that do not heal’ [17], and a gene expression profile that provides a ‘wound-response signature’ is predictive of local recurrence following breast-conserving surgery in breast cancer patients [18]. Such wound healing immune responses are characteristically associated with suppression of adaptive immune responses. M2 macrophages express a range of molecules associated with immune suppression, including arginase, IL-10 and TGF-β. Moreover, it is the constant proresolution and prowound healing environment caused by M2 tumor macrophages that combines to drive angiogenesis and thereby resistance to treatment, but also invasion and metastases [12]. Recent data demonstrated that immunotherapy with antibodies to CD40 improved the predicted effect of chemotherapy in pancreatic cancer patients [19]. Surprisingly, the mechanism did not occur via T-cell stimulation, but instead via anti-CD40-bound macrophages before their migration into the tumor, and resulted in a transient systemic surge in IFN-γ and TNF-α, but not IL-10, suggestive of M1 repolarization [19]. These data demonstrate that myeloid differentiation probably underpins many of the tumor features that limit effective therapy and represents an important potential target in cancer patients.It is important to note that cytokines derived from adaptive immune cells are the most potent agents directing macrophage polarization. We propose that the adaptive immune system is complicit in the development of the immune environment of tumors. CD4 T cells have been shown to contribute to tumor invasion and metastases by driving the late-stage M2 differentiation of tumor macrophages, via secretion of IL-4 [20]. However, T cells are also an important source of IFN-γ, which is a key cytokine for the M1 activation of macrophages. Repeated administration of tumor-specific effector T cells can remodel the tumor environment, resulting in reduced angiogenesis and normalization of the tumor vasculature [21]. Importantly, studies in colorectal cancer patients have shown that an IFN-γ gene signature and VEGF represent opposing predictors of recurrence [22]. Thus, while the primary intent of T-cell immunotherapy is to provide cell-mediated cytotoxicity to cancer cells, it is also possible that T-cell responses have the opportunity to enhance cytotoxic therapies through changes to the tumor environment, for example via local IFN-γ secretion. Cytotoxic T cells can eliminate tumors where they are unable to directly kill cancer cells, by targeting the tumor stroma [23]. Radiation and chemotherapy have been shown to cause transfer of antigens from cancer cells to macrophages in the tumor during a short window following cytotoxic therapy [24], and made these cells targets for tumor antigen-specific cytotoxic T cells. Stromal targeting was necessary for complete elimination of tumors where tumor antigen presentation was suboptimal [23], and required IFN-γ production by T cells and the IFN-γ receptor on macrophages and other stromal cells in the tumor [25]. We interpret these data to suggest that tumors may establish a permissive treatment environment, with IFN-γ, CD8 T cells and M1 differentiation of macrophages, versus a resistant tumor environment, with IL-4, angiogenesis and M2 differentiation of macrophages.This dichotomy represents an opportunity for immunotherapy. The vast majority of the cancer immunotherapy literature has studied techniques to increase tumor antigen-specific T-cell control of cancer cells. Unfortunately, immunotherapies alone have had limited success in the treatment of advanced or established cancers. Part of this limitation may be the limited ability of effector T cells to penetrate and function in the M2-dominated suppressive tumor environment. However, adaptive immunity can transiently change the tumor. Therapy with agonistic antibodies to the T-cell costimulatory molecule CD134 resulted in an increased influx of CD8 T cells into established murine tumors and, importantly, caused a simultaneous decrease in tumor macrophages, reducing immune suppression by those macrophages remaining [26]. Similarly, therapy with blocking antibodies to the negative regulatory molecule CD152 causes T-cell influxes to the tumor in mice [27] and in patients [28]. Thus, it is possible that immunotherapies, while limited in their efficacy as solo agents, may change the tumor environment to make conventional therapies more effective. We propose that adaptive immunity has the capacity to induce inflammatory-mediated changes in the tumor stroma, particularly via effects on tumor macrophages.In conclusion, we believe that there is considerable scope for trials of immunotherapy in combination with conventional therapy. The reality is that endogenous immune mechanisms already dictate how some patients respond to conventional therapy. We are only beginning to understand the immune component of conventional therapies, but there may already be many existing immunotherapies, ruled ineffective as single agents, that are capable of manipulating the tumor toward a favorable immune environment and could be effective in combination therapies. In addition, many targeted therapies that are ruled effective in preclinical models using xenograft testing may fail to adequately address the immune system’s role in the control of tumors following conventional therapies and this may explain in part the disparate effects seen when these agents transition into clinical trials.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1 Johnson JI, Decker S, Zaharevitz D et al. Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br. J. 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This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download