The Tumor Microenvironment and the Induction and Function of Tumor Specific T Cells

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It has become apparent that development of cancer is not simply a result of genetic alterations within the tumor but is associated with complex changes in host stromal, endothelial and inflammatory cells [42] The development of an invasive cancer involves increasing release of intracellular (endogeneous) danger signals from necrotic cells which is associated with the formation of a disordered tumor microenvironment. Such environment is characterized by promotion of angiogenesis and stromal proliferation and influences local immune responses.

It has become evident that cells dying by nonapoptotoc pathways (principally Necrosis) release substances that elicit host responses. Among these are the nuclear protein HMGB1, the S100 family of molecules, purinergic metabolites ATP, AMP adenosine and uric acid and heat shock proteins. Upon their release from the cytosol of necrotic cells they activate respective receptors on immune cells and result in significant immune responses [42]. S100 family members, secreted by macrophages at sites of inflammation are strongly enriched in a variety of tumors. They activate endothelial cells and phagocytes and serve as chemoattractants for tumor-infiltrating leukocytes. Purine metabolites, such as nucleosides and nucle-otides interact respectively with specialized P1 and P2 receptors of many immune effector cells. At low concentrations, these molecules enhance recruitment, maturation and emigration of antigen presenting cells via P1 receptors on immature DCs. However, on mature DCs, they are bound by P2 receptors. In this context, simultaneous binding of TLR9 by CpG diminishes the secretion of pro-inflammatory cytokines such as IL-12, IFN-alpha or IL-6 [42]. Uric acid augments the development of antigen specific T cells and maturates DCs for enhanced APC function. Heat shock proteins have been found to drive immune function and immune reactivity. These chaperones bind a broad variety of peptides, including those from TAAs, within the cytosol. Upon their release, they can be recognized by DCs, which leads to their efficient uptake, enhancement of presentation of antigenic peptides and DC maturation.

Lately, we have demonstrated surprisingly high frequencies of CTL in breast cancer patients recognizing HLA-restricted peptides from the matrix-degrading enzyme heparanase [43]. Increased expression and secretion of heparanase (Hpa)

by tumor cells promotes tumor invasion through extracellular matrices, tissue destruction, angiogenesis, and metastasis. Importantly, heparan-sulfates, the degradation products of heparanase are released at sites of inflammation, wound healing and tissue repair and can act as an endogenous activator of antigen presenting cells [43]. In tumor patients, they may represent a major "danger signal" that induces inflammation and T cell activation at sites of tumor metastasis.

The interplay between endogenous and exogenous danger signals determines an immune response during a pathogenic situation. Apoptotic cells can efficiently inhibit responses of immune cells against exogenous danger signals such as LPS or CpG-induced secretion of the pro-inflammatory cytokines IL-12 or TNF-alpha by promoting the secretion of TGF61 and IL-10. In contrast, the presence of endogenous danger signals released from necrotic cells in the vicinity of exogenous danger signals leads to more vigorous adaptive immune responses [42].

Although several studies report the implication of pro-inflammatory cytokines and chemokines as potentiators of carcinogenesis there is a growing body of evidence demonstrating the power of immunological protection from tumor growth [44]. Production of biologically active molecules by tumor cells includes hormones, prostaglandins, bioamines, NO, lactic acid, neuropeptides, ganglio-sides, cytokines, chemokines and growth factors [44]. By secretion of distinct patterns of these molecules tumors may be able to regulate the recruitment and activation of antigen presenting cells and thereby modulate the strength and type of a systemic antitumor immune response.

Up to date, little is known about the role of DCs in the natural immunosurveil-lance of cancer, although they are believed to play an essential role in the induction of tumor-specific T cell responses. Tumor-infiltrating DCs most likely play an important role in antitumor T cell immunity. First, increased numbers of tumor infiltrating DCs are associated with improved patient outcome with a variety of human tumors. For instance, in HNSCC, low numbers of tumor-infiltrating DC were a better predictor for poor prognosis than lymph node involvement [44]. Similarly, numbers of CD83+ DCs in liver metastases of colorectal carcinoma positively correlated with improved prognosis [44]. The loss of chemokine CXCL14 expression in human head and neck tumors was associated with decreased DC recruitment and deficient induction of antitumor immune responses [44]. MIP3alpha and GM-CSF were shown to recruit immature DCs to tumor sites and to increase natural antitumor T cell responses in mouse models [44]. Another cytokine which is released in tumor tissues by TIL and also by activated macrophages is TNF-a. TNF-alpha is required for the expression of C-C and CXC chemokines and subsequent recruitment of antigen presenting cells in a mouse model [45]. A prognostic relevance of intratumoral DCs can also be deduced from various observations of efficient tumor rejection after intratumoral DC injection [46]. The infiltration of tumors by DCs is of great importance in initiating the primary antitumor immune response and was confirmed as an independent prognostic parameter for survival in various cancer types.

One reason for the limited efficacy of the immune system to cope with tumors could be due to local suppression of DC, resulting in inhibition of antitumor T cell responses. This assumption is corroborated by frequent observations of reduced stimulatory capacities of circulating DCs from cancer patients. These exhibited reduced levels of HLA-II, CD11c, CD83, CD86 and reduced T cell stimulation capacity.

IL-10 and TGFfil are among the best characterized tumor-derived cytokines with immunosuppressive function. IL-10 is produced by many tumor cells and involved in regulating tumor cell proliferation, protection from immune recognition and immunosuppression [45]. IL-10 may inhibit CTL induction by downregulation of HLA class I and-II molecules and of ICAM-1 expression on DCs. The former may be due to an IL-10-mediated downregulation of TAP proteins. Moreover, IL-10 activated macrophages posses increased capacity to engulf apoptotic tumor cells, an anti-inflammatory process that suppresses T cell responses against respective antigens [42]. Recently, it was shown that IL-10 regulates the induction of an indoleamine-2,3-dioxygenase (IDO)-secreting DC subset. Interestingly, in combination with IL-10, IFN-y also increases IDO secretion. Thus, the presence of IL-10 can turn a proinflammatory signal into an immunosuppressive one [42]. Furthermore, IL-10 has been shown to promote the induction of T regulatory cells which may be also involved in the inhibition of DC-function through the release of TGF61. High concentrations of TGF61 are also frequently found in cancer patients and are associated with disease progression and poor responses to immunotherapy. TGF6 plays

Tumor Microenvironment Inflammatory

Fig. 3.2 Regulation of antitumor immune responses in the tumor microenvironment. DC; dendritic cell, LN; lymph node, HPA; heparanase, HSPG; heparane sulfate proteoglycan, TAM; tumor associated macrophage, Treg; regulatory T cell, HSPs; heat shock proteins, black arrows; migration into tumor tissue, grey, interrupted arrow; emigration from tumor tissue for T cell priming in lymphoid organs, black, interrupted arrows; release of substance, red arrows; activation of pro-inflammatory pathways, blue arrows; activation of inhibitory factors and pathways, blue lines; inhibition

Fig. 3.2 Regulation of antitumor immune responses in the tumor microenvironment. DC; dendritic cell, LN; lymph node, HPA; heparanase, HSPG; heparane sulfate proteoglycan, TAM; tumor associated macrophage, Treg; regulatory T cell, HSPs; heat shock proteins, black arrows; migration into tumor tissue, grey, interrupted arrow; emigration from tumor tissue for T cell priming in lymphoid organs, black, interrupted arrows; release of substance, red arrows; activation of pro-inflammatory pathways, blue arrows; activation of inhibitory factors and pathways, blue lines; inhibition an important role in regulating the activity of T cells and DCs in the tumor environment. These aspects of the regulation of antitumor immune responses in the tumor microenvironment are illustrated in Fig. 3.2.

The tumor microenvironment regulates antitumor immunity not only at the level of induction of systemic T cell responses but also regulates the infiltration and function in situ of tumor specific effector T cells. Numerous studies have demonstrated that tumor-infiltrating T cells exert reduced functional activity after their re-isolation from tumor tissue. They fail to be activated by TCR+ anti-CD28 stimulation under conditions that fully activate peripheral blood T cells [46]. TIL from colorectal carcinoma and from melanoma are anergic, express low TCR, perforin and Fas-L [47] and are deficient in perforin-mediated cytolytic activity due to defective microtubule organizing center mobilization and lytic granule exocytosis [48]. This is due to a combination of regulatory mechanisms in the tumor microenvironment and the lack of essential proinflammatory cytokines. T cell anergy due to insufficient B7 costim-ulation, extrinsic suppression by regulatory cell populations, inhibition by ligands such as programmed death ligand 1, metabolic deregulation by enzymes such as IDO, the action of soluble inhibitory factors such as TGF61 and IL-10 and tumor derived macrophage migration inhibitory factor (MIF) have been implicated in the generation of this suppressive environment [49, 50].

It has become apparent that in proportions of tumor patients the tumor microenvironment is not immunosuppressive and seems to support the induction of spontaneous T cell responses which apparently play, at least to some extend, a protective role. Tumor microenvironments thus seem to be heterogeneous. In addition to immunosuppressive factors, proinflammatory mechanisms may provide an immunological balance that is shifted in some patients in favor of type 1 T cell responses.

Such heterogeneity is seen also with tumor-associated macrophages (TAM). Two phenotypes have been characterized so far, namely Ml and M2. While Ml are characterized by secretion of cytotoxic substances such as NO and cytokines that support cell mediated cytotoxicity, the predominant population of TAM belongs to the M2 phenotype. These cells lack cytotoxic molecules, promote tumor cell proliferation and secrete T cell inhibitory cytokines, such as TGF6 and IL-10 and by the latter inhibit type 1 T cell immunity through the induction of T regulatory cells [51]. TAMs play moreover a major role in regulating fibrob-lasts with regard to their capacity to influence tumor cell growth through growth factor release [52].

Besides TAMs, tumor-infiltrating DCs may play an important role in maintaining functional T cells within the tumor environment. Cognate interactions between antigen-pulsed DCs and tumor-reactive T cells can inhibit apoptosis of T cells. On BM DCs such cognate interactions cause upregulation in the expression of CD83, MHC class II, CD40 and CD86 molecules and secretion of IL-12 and IFN-alpha. Adoptive transfer of breast cancer-reactive memory T cells together with APCs into human breast cancer-bearing NOD/SCID mice led to the generation of intratumoral clusters between transferred DCs, CD4 and CD8 T cells. This was associated with regression of the tumor and prolonged survival of the animals. When such animals had been treated by transfer of reactivated BM T cells without BM-DCs no tumor regression or prolonged survival was observed [21]. Thus, intratumoral, antigen-laden DCs may support the survival and function of tumor-infiltrating T cells. T lymphocytes are defective in cystine uptake and thus require exogenous thiols for activation and function. Upon cognate contact with T cells, antigen-presenting DCs release cysteine into the extracellular space and thereby contribute to a local microenvironment that facilitates immune responses. Il-12 derived from intratu-moral DCs may play an essential role for maintaining TIL function, since anergy and non-responsiveness of TIL could be reverted by culture in Il-12 [53, 54] and also by local IL-12 application. Such treatment induced spontaneous rejection of xenotransplanted human tumor pieces in NOD/Scid mice by co-transplanted intra-tumoral T cells and provoked in congenic tumor mouse models the establishment of protective systemic antitumor immunity. Besides IL-12, IL-6 secreted by TIL may be involved in the generation of a proinflammatory tumor microenvironment by inhibition of tumor-derived TGF61 and restoration of LAK activity in situ [55].

Taken together, tumors are regularly recognized by the immune system and endogenous danger signals released by necrotic tumor cells can promote the induction and accumulation of T cell responses in the bone marrow. The bone marrow parenchyma particularly mediates and supports protective T cell responses against blood borne TAAs and disseminated tumor cells. While type 1 T cell responses seem to occur in virtually all tumor entities, they are generally restricted to proportions of patients. A pronounced heterogeneity in the molecular composition of the tumor microenvironment may determine the net result of either presence or absence of type 1 T cell responses in individual patients. The tumor microenvironment obviously regulates antitumor immunity at several levels: (i) induction of systemic T cell responses, (ii) T cell infiltration and (iii) T cell function. The individual level of pro- and anti-inflammatory factors in the tumor tissue may provide the key to the type of immune response occurring.

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