Immune regulation of cancer Disis, Mary L
Journal of clinical oncology,
10/2010, Letnik:
28, Številka:
29
Journal Article
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Innate and adaptive immune system cells play a major role in regulating the growth of cancer. Although it is commonly thought that an immune response localized to the tumor will inhibit cancer ...growth, it is clear that some types of inflammation induced in a tumor may also lead to cancer proliferation, invasion, and dissemination. Recent evidence suggests, however, that some patients with cancer can mount an antitumor immune response that has the potential to control or eliminate cancer. Indeed, a so-called "immune response" signature has been described in malignancy that is associated with improved outcomes in several tumor types. Moreover, the presence of specific subsets of T cells, which have the capability to penetrate tumor stroma and infiltrate deep into the parenchyma, identifies patients with an improved prognosis. Immune-based therapies have the potential to modulate the tumor microenvironment by eliciting immune system cells that will initiate acute inflammation that leads to tissue destruction.
Tumor infiltrating lymphocytes (TIL) play an essential role in mediating response to chemotherapy and improving clinical outcomes in all subtypes of breast cancer. Triple negative breast cancers (TN) ...are most likely to have tumors with >50 % lymphocytic infiltrate, termed lymphocyte predominant breast cancer, and derive the greatest survival benefit from each 10 % increase in TIL. The majority of HER2+ breast cancers have similar level of immune infiltrate as TN breast cancer yet the presence of TILs has not shown the same survival benefit. For HER2+ breast cancers, type 1 T-cells, either increased TBET+ tumor infiltration or increased type 1 HER2-specific CD4+ T-cells in the peripheral blood, are associated with better outcomes. Hormone receptor positive HER2 negative tumors tend to have the least immune infiltrate yet are the only breast cancer subtype to show worse prognosis with increased FOXP3 regulatory T-cell infiltrate. Notably, all breast cancer subtypes have tumors with low, intermediate, or high TIL infiltrate. Tumors with high TILs may also have increased PD-L1 expression which might be the reason that TN breast cancer seems to demonstrate the most robust clinical response to immune checkpoint inhibitor therapy but further investigation is needed. Tumors with intermediate or low levels of pre-treatment immune infiltrate, on the other hand, may benefit from an intervention that may increase TIL, particularly type 1 T-cells. Examples of these interventions include specific types of cytotoxic chemotherapy, radiation, or vaccine therapy. Therefore, the systematic evaluation of TIL and specific populations of TIL may be able to both guide prognosis and the appropriate sequencing of therapies in breast cancer.
The immune system plays a vital role in regulating the growth of tumors. Some types of inflammatory responses can promote tumor growth, while a tumor-specific adaptive immune response can potentially ...control tumor growth. Malignancies have the ability to evade the immune system, and proliferate and metastasize. The goal of immunotherapy is to marshal the specificity and long-term memory of the adaptive immune response to achieve durable tumor regression and possible cure, although, to date, this has been achieved in only a small subset of patients. A variety of approaches to immunotherapy have been investigated. These include administration of exogenous cytokines or therapeutic vaccines to increase the frequency of tumor-specific T cells, adoptive transfer of tumor-specific immune effector cells, and, more recently, the application of a variety of immune checkpoint inhibitors and agonists of co-stimulatory receptors to overcome tumor-induced immune-suppressive mechanisms. Some approaches have been more successful than others for reasons that are now becoming apparent, and these observations have led to an exciting resurgence in clinical research to develop more effective immunotherapeutic strategies.
The toxicities of immunotherapy for cancer are as diverse as the type of treatments that have been devised. These range from cytokine therapies that induce capillary leakage to vaccines associated ...with low levels of autoimmunity to cell therapies that can induce damaging cross-reactivity with normal tissue to checkpoint protein inhibitors that induce immune-related adverse events that are autoinflammatory in nature. The thread that ties these toxicities together is their mechanism-based immune nature and the T-cell-mediated adverse events seen. The basis for the majority of these adverse events is a hyperactivated T-cell response with reactivity directed against normal tissue, resulting in the generation of high levels of CD4 T-helper cell cytokines or increased migration of cytolytic CD8 T cells within normal tissues. The T-cell immune response is not tissue specific and may reflect a diffuse expansion of the T-cell repertoire that induces cross-reactivity with normal tissue, effectively breaking tolerance that is active with cytokines, vaccines, and checkpoint protein inhibitors and passive in the case of adoptive cell therapy. Cytokines seem to generate diffuse and nonspecific T-cell reactivity, whereas checkpoint protein inhibition, vaccines, and adoptive cell therapy seem to activate more specific T cells that interact directly with normal tissues, potentially causing specific organ damage. In this review, we summarize the toxicities that are unique to immunotherapies, emphasizing the need to familiarize the oncology practitioner with the spectrum of adverse events seen with newly approved and emerging modalities.
Over the last few years, several newly developed immune-based cancer therapies have been shown to induce clinical responses in significant numbers of patients. As a result, there is a need to ...identify immune biomarkers capable of predicting clinical response. If there were laboratory parameters that could define patients with improved disease outcomes after immunomodulation, product development would accelerate, optimization of existing immune-based treatments would be facilitated and patient selection for specific interventions might be optimized. Although there are no validated cancer immunologic biomarkers that are predictive of clinical response currently in widespread use, there is much published literature that has informed investigators as to which markers may be the most promising. Population-based studies of endogenous tumor immune infiltrates and gene expression analyses have identified specific cell populations and phenotypes of immune cells that are most likely to mediate anti-tumor immunity. Further, clinical trials of cancer vaccines and other cancer directed immunotherapy have identified candidate immunologic biomarkers that are statistically associated with beneficial clinical outcomes after immune-based cancer therapies. Biomarkers that measure the magnitude of the Type I immune response generated with immune therapy, epitope spreading, and autoimmunity are readily detected in the peripheral blood and, in clinical trials of cancer immunotherapy, have been associated with response to treatment.
The presence of tumor-infiltrating lymphocytes (TILs) is a favorable prognostic factor in breast cancer, and TILs may synergize with chemotherapy and immune checkpoint inhibitor therapy for improved ...clinical response. A more detailed understanding of the variation in lymphocytic infiltration in breast cancer may aid in identifying subtypes more amenable to immunomodulation.
To determine the median percentage of patients with breast cancer with no, intermediate, or high levels of TIL and assess variations in lymphocytic cell subsets across breast cancer subtypes.
Eligible studies (PubMed, 1990-2015) analyzed tumor lymphocytic, CD8+, and FOXP3+ cellular infiltrates, and used multivariable analyses and quantitative methods for enumerating cell populations. Selection of of studies was performed in accordance with PRISMA guidelines and evaluated by 2 independent appraisers.
Fifteen studies (n = 13 914) met prespecified criteria and were reviewed in December 2015. A median of 11% (range, 5%-26%) of breast cancers demonstrate lymphocyte-predominant breast cancer (LPBC), with approximately 16% of cancers showing no evidence of TILs. Triple-negative (TN) breast cancers demonstrated the highest incidence of LPBC (20%; range, 4%-37%). This incidence is similar to that of breast cancers that are human epidermal growth factor 2 positive and either hormone receptor positive or negative (HER2+) at 16% (range 11%-24%). Hormone receptor positive/HER2- (HR+) breast cancer showed the lowest incidence of LPBC at 6% (range, 3%-12%). CD8+ T-cell infiltrates, indicative of type I immunity, were found in 48% of all breast cancers (range, 32%-80%) with similar levels observed in TN (60%; range, 40%-91%) and HER2+ disease (61%; range, 40%-83%). Fewer HR+ tumors demonstrated CD8+ TIL (43%; range, 30%-73%). The highest levels of FOXP3+ cells were observed in TN (70%; range, 65%-76%) and HER2+ disease (67%; range, 61%-74%). A minority of HR+ breast cancers demonstrated high levels of tumor-infiltrating FOXP3+ cells (38%; range, 35%-41%).
The magnitude of TIL is variable within and between breast cancer subtypes. Levels of lymphocytic subpopulations may identify breast cancers more amenable to immunomodulation and indicate additional strategies to enhance immunity in patients with low to moderate levels of TILs.
Current success of immunotherapy in cancer has drawn attention to the subsets of T
H
cells in the tumor which are critical for activation of anti-tumor response either directly by themselves or by ...stimulating cytotoxic T cell activity. However, presence of immunosuppressive pro-tumorigenic T
H
subsets in the tumor milieu further contributes to the complexity of regulation of T
H
cell-mediated immune response. In this review, we present an overview of the multifaceted positive and negative effects of T
H
cells, with an emphasis on regulation of different T
H
cell subtypes by various immune cells, and how a delicate balance of contradictory signals can influence overall success of cancer immunotherapy. We focus on the regulatory network that encompasses dendritic cell-induced activation of CD4
+
T
H
1 cells and subsequent priming of CD8
+
cytotoxic T cells, along with intersecting anti-inflammatory and pro-tumorigenic T
H
2 cell activity. We further discuss how other tumor infiltrating immune cells such as immunostimulatory T
H
9 and T
fh
cells, immunosuppressive T
reg
cells, and the duality of T
H
17 function contribute to tip the balance of anti- vs pro-tumorigenic T
H
responses in the tumor. We highlight the developing knowledge of CD4
+
T
H
1 immune response against neoantigens/oncodrivers, impact of current immunotherapy strategies on CD4
+
T
H
1 immunity, and how opposing action of T
H
cell subtypes can be explored further to amplify immunotherapy success in patients. Understanding the nuances of CD4
+
T
H
cells regulation and the molecular framework undergirding the balancing act between anti- vs pro-tumorigenic T
H
subtypes is critical for rational designing of immunotherapies that can bypass therapeutic escape to maximize the potential of immunotherapy.
Death by Gun Violence-A Public Health Crisis Bauchner, Howard; Rivara, Frederick P; Bonow, Robert O ...
JAMA : the journal of the American Medical Association,
11/2017, Letnik:
318, Številka:
18
Journal Article
Current success of immunotherapy in cancer has drawn attention to the subsets of T
cells in the tumor which are critical for activation of anti-tumor response either directly by themselves or by ...stimulating cytotoxic T cell activity. However, presence of immunosuppressive pro-tumorigenic T
subsets in the tumor milieu further contributes to the complexity of regulation of T
cell-mediated immune response. In this review, we present an overview of the multifaceted positive and negative effects of T
cells, with an emphasis on regulation of different T
cell subtypes by various immune cells, and how a delicate balance of contradictory signals can influence overall success of cancer immunotherapy. We focus on the regulatory network that encompasses dendritic cell-induced activation of CD4
T
1 cells and subsequent priming of CD8
cytotoxic T cells, along with intersecting anti-inflammatory and pro-tumorigenic T
2 cell activity. We further discuss how other tumor infiltrating immune cells such as immunostimulatory T
9 and T
cells, immunosuppressive T
cells, and the duality of T
17 function contribute to tip the balance of anti- vs pro-tumorigenic T
responses in the tumor. We highlight the developing knowledge of CD4
T
1 immune response against neoantigens/oncodrivers, impact of current immunotherapy strategies on CD4
T
1 immunity, and how opposing action of T
cell subtypes can be explored further to amplify immunotherapy success in patients. Understanding the nuances of CD4
T
cells regulation and the molecular framework undergirding the balancing act between anti- vs pro-tumorigenic T
subtypes is critical for rational designing of immunotherapies that can bypass therapeutic escape to maximize the potential of immunotherapy.
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