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Boosting the MHC Class II-Restricted Tumor Antigen Presentation to CD4+ T Helper Cells: A Critical Issue for Triggering Protective Immunity and Re-Orienting the Tumor Microenvironment Toward an Anti-Tumor State.

Accolla RS, Lombardo L, Abdallah R, Raval G, Forlani G, Tosi G - Front Oncol (2014)

Bottom Line: Over the years many investigators have described strategies to rescue the anti-tumor immune response with the aim of creating specific and long-lasting protection against the disease.When exported to human clinical settings, these strategies have revealed in most cases a very limited, if any, positive outcome.Within this frame, therefore, we believe that the establishment of a pro-tumor environment is not the cause but simply the consequence of the tumor strategy to primarily counteract components of the adaptive cellular immunity, particularly TH lymphocytes.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgical and Morphological Sciences, University of Insubria , Varese , Italy.

ABSTRACT
Although the existence of an immune response against tumor cells is well documented, the fact that tumors take off in cancer patients indicates that neoplastic cells can circumvent this response. Over the years many investigators have described strategies to rescue the anti-tumor immune response with the aim of creating specific and long-lasting protection against the disease. When exported to human clinical settings, these strategies have revealed in most cases a very limited, if any, positive outcome. We believe that the failure is mostly due to the inadequate triggering of the CD4+ T helper (TH) cell arm of the adaptive immunity, as TH cells are necessary to trigger all the immune effector mechanisms required to eliminate tumor cells. In this review, we focus on novel strategies that by stimulating MHC class II-restricted activation of TH cells generate a specific and persistent adaptive immunity against the tumor. This point is of critical importance for both preventive and therapeutic anti-tumor vaccination protocols, because adaptive immunity with its capacity to produce specific, long-lasting protection and memory responses is indeed the final goal of vaccination. We will discuss data from our as well as other laboratories which strongly suggest that triggering a specific and persistent anti-tumor CD4+ TH cell response stably modify not only the tumor microenvironment but also tumor-dependent extratumor microenvironments by eliminating and/or reducing the blood-derived tumor infiltrating cells that may have a pro-tumor growth function such as regulatory CD4+/CD25+ T cells and myeloid-derived-suppressor cells. Within this frame, therefore, we believe that the establishment of a pro-tumor environment is not the cause but simply the consequence of the tumor strategy to primarily counteract components of the adaptive cellular immunity, particularly TH lymphocytes.

No MeSH data available.


Related in: MedlinePlus

The key actions for establishing a protective anti-tumor immunity against cancer. The immune response against cancer is put on break by several mechanisms among which tumor antigen availability and stimulation of MHC class II-restricted CD4+ TH cells are key features (upper part of the Figure). Insufficient tumor antigen availability and/or insufficient MHC-II–tumor peptide complexes (cumulatively defined as adequate antigen availability or AAA) lead to insufficient stimulation of TH cells. This results in lack of immune effector responses which may favor the establishment of immune suppressor mechanism on anti-tumor responses, such as polarization of TH responses toward a TH2 phenotype, activation and increase number of regulatory T cells (Treg) and myeloid-derived-suppressor cells (MDSC), which cumulatively create a pro-tumor polarization of the tumor microenvironment. Presence of AAA (lower part of the Figure) generated, for example, by MHC class II expression in tumor cells or by therapy-induced immunogenic cell death efficiently triggers tumor specific TH cells and this is instrumental to both activate immune effector mechanisms such as CTL and repress and/or prevent suppressor mechanisms on protective immunity. This results in the generation of an anti-tumor microenvironment and in a strong adaptive immune response against the tumor.
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Figure 1: The key actions for establishing a protective anti-tumor immunity against cancer. The immune response against cancer is put on break by several mechanisms among which tumor antigen availability and stimulation of MHC class II-restricted CD4+ TH cells are key features (upper part of the Figure). Insufficient tumor antigen availability and/or insufficient MHC-II–tumor peptide complexes (cumulatively defined as adequate antigen availability or AAA) lead to insufficient stimulation of TH cells. This results in lack of immune effector responses which may favor the establishment of immune suppressor mechanism on anti-tumor responses, such as polarization of TH responses toward a TH2 phenotype, activation and increase number of regulatory T cells (Treg) and myeloid-derived-suppressor cells (MDSC), which cumulatively create a pro-tumor polarization of the tumor microenvironment. Presence of AAA (lower part of the Figure) generated, for example, by MHC class II expression in tumor cells or by therapy-induced immunogenic cell death efficiently triggers tumor specific TH cells and this is instrumental to both activate immune effector mechanisms such as CTL and repress and/or prevent suppressor mechanisms on protective immunity. This results in the generation of an anti-tumor microenvironment and in a strong adaptive immune response against the tumor.

Mentions: We have seen how either preventive or therapeutic anti-tumor modalities may generate an anti-tumor immune response that in many cases strongly contribute to the modification of the tumor microenvironment and to the eradication of the neoplastic lesion. These results give strong support to the idea that a correct stimulation of the immune system, particularly of the adaptive arm of it, constitutes a primary strategy to be pursued for combating and defeating cancer (see Figure 1). With the exception of preventive vaccination approaches whose final goal is indeed to primarily trigger the adaptive immune system and generate long-lasting immunity against cancer, other classical therapeutic approaches have unveiled the participation of different components of the immune system to a possible successful outcome upon therapy. Recent excellent reviews have summarized the mechanisms and the distinct components of the immune systems that are involved in such therapeutic approaches (46, 54, 71). However, the many possible players that the immune system may use for either triggering a positive response or counteracting a suppressive response against the tumor are not, in our opinion, equally important for the elicitation of a protective immune response against cancer. Based on our experience and on the results of many groups described in this review, we believe that a crucial and hierarchically predominant step is constituted by the efficacy of MHC class II-restricted tumor antigen presentation to CD4+ TH cells (see Figure 2). We have defined this step as AAA to indicate the optimal tumor antigen dose and related antigen processing and MHC-II-restricted presentation necessary to efficiently trigger tumor-specific TH cells (12). We have shown that AAA can be obtained in several ways either by inducing MHC class II expression in tumor cells by transfection with the AIR-1 gene-encoded MHC CIITA, thus providing functionally sufficient MHC-II–tumor peptide complexes for TH cell scrutiny, or by increasing the availability of tumor antigens by specific treatment of established tumors with L19mTNFα. The fundamental finding of both approaches was the elicitation of long-lived anti-tumor specific TH cells capable to eradicate the tumor and to protect the host against further tumor challenge. The primary importance of AAA in the hierarchic scale of anti-tumor immunity stems also from the fact that the correct triggering of TH cells was sufficient to unleash the chain of events leading to a strong effector CTL response and to the abrogation or, at least, the attenuation of suppressor mechanisms operating on the anti-tumor immune response (Figure 1). Moreover, and importantly, the optimal initiation of the adaptive immune response dictated by AAA was sufficient to reorient the tumor microenvironment from a pro-tumor to an anti-tumor microenvironment. Thus, in a sort of re-edition of the immunological homunculus theory originally proposed by Cohen to explain autoimmunity (72), we propose that most of the protective control exerted by the adaptive immune system on cancer derives from AAA (APC and MHC-II, the hand in Figure 2) and consequent activation of tumor specific TH cells (the face in Figure 2).


Boosting the MHC Class II-Restricted Tumor Antigen Presentation to CD4+ T Helper Cells: A Critical Issue for Triggering Protective Immunity and Re-Orienting the Tumor Microenvironment Toward an Anti-Tumor State.

Accolla RS, Lombardo L, Abdallah R, Raval G, Forlani G, Tosi G - Front Oncol (2014)

The key actions for establishing a protective anti-tumor immunity against cancer. The immune response against cancer is put on break by several mechanisms among which tumor antigen availability and stimulation of MHC class II-restricted CD4+ TH cells are key features (upper part of the Figure). Insufficient tumor antigen availability and/or insufficient MHC-II–tumor peptide complexes (cumulatively defined as adequate antigen availability or AAA) lead to insufficient stimulation of TH cells. This results in lack of immune effector responses which may favor the establishment of immune suppressor mechanism on anti-tumor responses, such as polarization of TH responses toward a TH2 phenotype, activation and increase number of regulatory T cells (Treg) and myeloid-derived-suppressor cells (MDSC), which cumulatively create a pro-tumor polarization of the tumor microenvironment. Presence of AAA (lower part of the Figure) generated, for example, by MHC class II expression in tumor cells or by therapy-induced immunogenic cell death efficiently triggers tumor specific TH cells and this is instrumental to both activate immune effector mechanisms such as CTL and repress and/or prevent suppressor mechanisms on protective immunity. This results in the generation of an anti-tumor microenvironment and in a strong adaptive immune response against the tumor.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927100&req=5

Figure 1: The key actions for establishing a protective anti-tumor immunity against cancer. The immune response against cancer is put on break by several mechanisms among which tumor antigen availability and stimulation of MHC class II-restricted CD4+ TH cells are key features (upper part of the Figure). Insufficient tumor antigen availability and/or insufficient MHC-II–tumor peptide complexes (cumulatively defined as adequate antigen availability or AAA) lead to insufficient stimulation of TH cells. This results in lack of immune effector responses which may favor the establishment of immune suppressor mechanism on anti-tumor responses, such as polarization of TH responses toward a TH2 phenotype, activation and increase number of regulatory T cells (Treg) and myeloid-derived-suppressor cells (MDSC), which cumulatively create a pro-tumor polarization of the tumor microenvironment. Presence of AAA (lower part of the Figure) generated, for example, by MHC class II expression in tumor cells or by therapy-induced immunogenic cell death efficiently triggers tumor specific TH cells and this is instrumental to both activate immune effector mechanisms such as CTL and repress and/or prevent suppressor mechanisms on protective immunity. This results in the generation of an anti-tumor microenvironment and in a strong adaptive immune response against the tumor.
Mentions: We have seen how either preventive or therapeutic anti-tumor modalities may generate an anti-tumor immune response that in many cases strongly contribute to the modification of the tumor microenvironment and to the eradication of the neoplastic lesion. These results give strong support to the idea that a correct stimulation of the immune system, particularly of the adaptive arm of it, constitutes a primary strategy to be pursued for combating and defeating cancer (see Figure 1). With the exception of preventive vaccination approaches whose final goal is indeed to primarily trigger the adaptive immune system and generate long-lasting immunity against cancer, other classical therapeutic approaches have unveiled the participation of different components of the immune system to a possible successful outcome upon therapy. Recent excellent reviews have summarized the mechanisms and the distinct components of the immune systems that are involved in such therapeutic approaches (46, 54, 71). However, the many possible players that the immune system may use for either triggering a positive response or counteracting a suppressive response against the tumor are not, in our opinion, equally important for the elicitation of a protective immune response against cancer. Based on our experience and on the results of many groups described in this review, we believe that a crucial and hierarchically predominant step is constituted by the efficacy of MHC class II-restricted tumor antigen presentation to CD4+ TH cells (see Figure 2). We have defined this step as AAA to indicate the optimal tumor antigen dose and related antigen processing and MHC-II-restricted presentation necessary to efficiently trigger tumor-specific TH cells (12). We have shown that AAA can be obtained in several ways either by inducing MHC class II expression in tumor cells by transfection with the AIR-1 gene-encoded MHC CIITA, thus providing functionally sufficient MHC-II–tumor peptide complexes for TH cell scrutiny, or by increasing the availability of tumor antigens by specific treatment of established tumors with L19mTNFα. The fundamental finding of both approaches was the elicitation of long-lived anti-tumor specific TH cells capable to eradicate the tumor and to protect the host against further tumor challenge. The primary importance of AAA in the hierarchic scale of anti-tumor immunity stems also from the fact that the correct triggering of TH cells was sufficient to unleash the chain of events leading to a strong effector CTL response and to the abrogation or, at least, the attenuation of suppressor mechanisms operating on the anti-tumor immune response (Figure 1). Moreover, and importantly, the optimal initiation of the adaptive immune response dictated by AAA was sufficient to reorient the tumor microenvironment from a pro-tumor to an anti-tumor microenvironment. Thus, in a sort of re-edition of the immunological homunculus theory originally proposed by Cohen to explain autoimmunity (72), we propose that most of the protective control exerted by the adaptive immune system on cancer derives from AAA (APC and MHC-II, the hand in Figure 2) and consequent activation of tumor specific TH cells (the face in Figure 2).

Bottom Line: Over the years many investigators have described strategies to rescue the anti-tumor immune response with the aim of creating specific and long-lasting protection against the disease.When exported to human clinical settings, these strategies have revealed in most cases a very limited, if any, positive outcome.Within this frame, therefore, we believe that the establishment of a pro-tumor environment is not the cause but simply the consequence of the tumor strategy to primarily counteract components of the adaptive cellular immunity, particularly TH lymphocytes.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgical and Morphological Sciences, University of Insubria , Varese , Italy.

ABSTRACT
Although the existence of an immune response against tumor cells is well documented, the fact that tumors take off in cancer patients indicates that neoplastic cells can circumvent this response. Over the years many investigators have described strategies to rescue the anti-tumor immune response with the aim of creating specific and long-lasting protection against the disease. When exported to human clinical settings, these strategies have revealed in most cases a very limited, if any, positive outcome. We believe that the failure is mostly due to the inadequate triggering of the CD4+ T helper (TH) cell arm of the adaptive immunity, as TH cells are necessary to trigger all the immune effector mechanisms required to eliminate tumor cells. In this review, we focus on novel strategies that by stimulating MHC class II-restricted activation of TH cells generate a specific and persistent adaptive immunity against the tumor. This point is of critical importance for both preventive and therapeutic anti-tumor vaccination protocols, because adaptive immunity with its capacity to produce specific, long-lasting protection and memory responses is indeed the final goal of vaccination. We will discuss data from our as well as other laboratories which strongly suggest that triggering a specific and persistent anti-tumor CD4+ TH cell response stably modify not only the tumor microenvironment but also tumor-dependent extratumor microenvironments by eliminating and/or reducing the blood-derived tumor infiltrating cells that may have a pro-tumor growth function such as regulatory CD4+/CD25+ T cells and myeloid-derived-suppressor cells. Within this frame, therefore, we believe that the establishment of a pro-tumor environment is not the cause but simply the consequence of the tumor strategy to primarily counteract components of the adaptive cellular immunity, particularly TH lymphocytes.

No MeSH data available.


Related in: MedlinePlus