Cancer Immunoprevention Research Articles

Abstract 1418: Marine ω-3 polyunsaturated fatty acid intake and risk of colorectal cancer according to tumor-infiltrating T cells

Abstract Importance: Marine ω-3 polyunsaturated fatty acids possess potent immunomodulatory activity and may protect against cancer development. However, evidence relating marine ω-3 polyunsaturated fatty acids to colorectal cancer risk remains inconclusive. Objective: To test the hypothesis that marine ω-3 polyunsaturated fatty acid intake may be associated with lower risk of colorectal cancer subsets characterized by immune infiltrate. Design: Prospective cohort study Setting: Nurses’ Health Study and Health Professionals Follow-up Study Participants: In the two cohorts, 125,172 participants provided data about marine ω-3 polyunsaturated fatty acid intake every 4 years through a validated food frequency questionnaire and followed up for incident colorectal cancer over 24-26 years. We documented 614 colorectal cancer cases from which we could assess T-cell infiltration in the tumor microenvironment. Cause-specific Cox proportional hazards regression was used to estimate hazard ratios and 95% confidence intervals for risks of colorectal cancer subtypes. Exposure: Intake of marine ω-3 polyunsaturated fatty acids Main Outcome and Measures: Incidence of colorectal cancer according to tumor-infiltrating T cells Results: The inverse association of marine ω-3 polyunsaturated fatty acids with colorectal cancer risk differed according to FOXP3+ T-cell infiltration (P for heterogeneity = 0.006). Compared to intake of <0.15 g/day of marine ω-3 PUFAs, intake of ≥0.35 g/day was associated with a multivariable hazard ratio of 0.57 (95% confidence interval, 0.40 to 0.81) (P for trend < 0.001) for FOXP3+ T-cell-high tumors. In contrast, the corresponding hazard ratio was 1.14 (95% confidence interval, 0.81 to 1.60) (P for trend = 0.77) for FOXP3+ T-cell-low tumors. No statistically significant differential association was found according to tumor-infiltrating CD3+, CD8+, or CD45RO+ T cells (P for heterogeneity ≥ 0.34). In functional assays, the suppressive activity of regulatory T cells was approximately two-fold lower when pre-incubated with marine ω-3 polyunsaturated fatty acids at 50, 100 and 200 μM than without marine ω-3 polyunsaturated fatty acids (P<0.0001). Conclusion and Relevance: High marine ω-3 polyunsaturated fatty acid intake was associated with lower risk of colorectal cancer with high-level, but not low-level, FOXP3+ T-cell density, suggesting a potential role of ω-3 polyunsaturated fatty acids in cancer immunoprevention through modulation of regulatory T cells. Citation Format: Mingyang Song, Reiko Nishihara, Yin Cao, Eunyoung Chun, Zhi Rong Qian, Kosuke Mima, Kentaro Inamura, Yohei Masugi, Jonathan Nowak, Katsuhiko Nosho, Kana Wu, Molin Wang, Edward Giovannucci, Wendy S. Garrett, Charles S. Fuchs, Shuji Ogino, Andrew T. Chan. Marine ω-3 polyunsaturated fatty acid intake and risk of colorectal cancer according to tumor-infiltrating T cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1418.

Postmenopausal Breast Cancer Risk in Relation to Antibodies Specific to Benzo[a]Pyrene, Estradiol and Progesterone.

BackgroundAntibodies might protect against low doses of environmental carcinogens by decreasing systemic uptake, activation of metabolic pathways, and redistribution of carcinogens within the organism. The features of antibody formation in relation to environmental carcinogens and sex steroids under natural conditions should be determined to identify breast cancer risk, then to develop cancer immune prevention strategies.ObjectivesThe purpose of this study was to investigate antibodies specifications to benzo(a)pyrene, estradiol and progesterone in postmenopausal women with invasive breast cancer.Patients and MethodsA semi-quantitative non-competitive immunoassay of IgG antibodies to benzo(a)pyrene (IgG-Bp), estradiol (IgG-Es), and progesterone (IgG-Pg) has conducted. The assay has performed on 322 serum samples from patients with breast cancer and 179 serum samples from healthy postmenopausal women by using low-molecular-weight Bp, Es, and Pg conjugated with bovine serum albumin. ROC analysis has also conducted to determine the odds ratio (OR).ResultsCombination of the high levels of IgG-Bp and IgG-Es without IpG-Pg was more frequent in breast cancer patients than that in healthy women, and the OR has increased to 3.8. Combination of the high levels of IgG-Pg with high levels of both IgG-Bp and IgG-Es were significantly more frequent in breast cancer patients (36.9%) than that in healthy women (5.6%), and the OR increased to 11.7. These differences have peculiarly expressed in breast cancer patients with hormone status ER+/PR- (OR = 26.7). The minimum OR (0.4) has obtained at low levels of the three antibodies.ConclusionsImmunoassay of antibodies against environmental carcinogens and sex steroid hormones could use to detect breast cancer risk. Induction of antibodies against Bp for cancer immunoprevention could lead to antibody formation against steroid hormones, thereby increasing breast cancer risk.

Emerging strategies for cancer immunoprevention.

The crucial role of the immune system in the formation and progression of tumors has been widely accepted. On one hand, the surveillance role of the immune system plays an important role in endogenous tumor prevention, but on the other hand, in some special circumstances such as in chronic inflammation, the immune system can actually contribute to the formation and progression of tumors. In recent years, there has been an explosion of novel targeted immunotherapies for advanced cancers. In the present manuscript, we explore known and potential various types of cancer prevention strategies and focus on nonvaccine-based cancer preventive strategies targeting the immune system at the early stages of tumorigenesis.

Abstract PL04-03: Fatal Attraction: A new story featuring the immune system and pancreatic cancer

Abstract Until recently, barriers to immunotherapy clinical successes for pancreatic cancer have been due to a lack of understanding of the immune pathways within the pancreatic tumor microenvironment that hinder successful immune responses. Recent advances have identified new targets for developing cancer specific vaccines and new targets for modulating the tumor microenvironment to allow more potent activation and improved access of vaccine induced immune responses. We are just learning that non-neoplastic cells, including cancer-associated myofibroblasts, regulatory T cells, dendritic cells, myeloid-derived suppressor cells, and tumor-associated macrophages, are hijacked by pre-invasive and invasive cancer cells to create a tolerogenic tumor microenvironment. Current research is focused on elucidating the mechanisms of this tolerogenic polarization within the tumor microenvironment with the goal of tipping the balance in favor of an anticancer immune response. With the recent advances in molecular technologies and the development of relevant pancreatic cancer mouse models, it is now within our reach to dissect the inhibitory pathways within the pancreatic tumor microenvironment. This will in turn, lead to new therapeutic opportunities that will eliminate these barriers and convert this deadly cancer into a treatable disease. Building on our extensive experience developing immunotherapies for pancreatic cancer, we are now developing combinatorial immunotherapies that combine T cell inducing agents with agents that modulate T cell down regulatory signals within the tumor microenvironment. These studies have shown for the first time that traditionally “non-immunogenic” cancers that do not respond to single agent immune modulating agents, can be converted into tumors susceptible to these agents if a T cell inducing vaccine is given together with these immune modulating agents. Results from both pre-clinical and clinical studies will be discussed.

Nonviral oncogenic antigens and the inflammatory signals driving early cancer development as targets for cancer immunoprevention.

Cancer immunoprevention is an emerging field that holds much promise. Within the past 20 years, prophylactic vaccines have been implemented on the population level for the immunoprevention of carcinomas induced by viruses, specifically hepatitis B virus (HBV) and human papillomavirus (HPV) infection. Armed with the success of prophylactic vaccines that prevent viral-induced tumors, the field must overcome its next hurdle: to develop robust prophylactic vaccines that prevent the remaining >80% of human cancers not induced by viral infection. In this review, we discuss some of the most promising non-virus-associated prophylactic vaccines that target endogenous neoantigens, including the earliest oncogene products, altered mucin 1 (MUC1) and α-enolase (ENO1), all of which produce new targets in the earliest stages of nonviral-induced tumorigenesis. We also highlight a novel attenuated Listeria monocytogenes-based vaccine expressing mutant oncogene Kras(G12D) (LM-Kras) effective in a pancreatic cancer model. A novel chimeric human/rat HER-2 plasmid vaccine (HuRT-DNA vaccine) effective in a breast cancer model is also discussed. In addition to prophylactic vaccine developments, this review highlights the potential use of classic drugs, such as aspirin and metformin, as chemopreventive agents that can potentially be used as adjuvants to enhance the anticancer immunogenicity and efficacy of noninfectious prophylactic vaccines by modulating the inflammatory pathways within the early tumor microenvironment (TME) that propels tumorigenesis. Finally, timing of prophylactic vaccine administration is critical to its immunopreventive efficacy, providing a necessary role of current and emerging biomarkers for cancer screening and early cancer detection.

Plasma 25-hydroxyvitamin D and colorectal cancer risk according to tumour immunity status

ObjectiveEvidence suggests protective effects of vitamin D and antitumour immunity on colorectal cancer risk. Immune cells in tumour microenvironment can convert 25-hydroxyvitamin D [25(OH)D] to bioactive 1α,25-dihydroxyvitamin D3, which influences...

"Omics" and Immunologic Approaches to Optimizing Cure Rates in HER2-Positive Breast Carcinomas.

"Omics" and Immunologic Approaches to Optimizing Cure Rates in HER2-Positive Breast Carcinomas.

Cancer immunoprevention: a new approach to intercept cancer early.

Cancer immunoprevention refers to the modulation of the host immune response to control the initiation or development of cancer. The significant role of host immunity in early tumorigenesis has only recently been confirmed, as a better understanding of the mechanisms, molecules and cells involved in tumor immunology have been elucidated over the past two decades. Of utmost importance, preclinical and clinical evidences have demonstrated that early neoplastic cells (transformed cells that initiate cancer formation) express antigens that allow the immune system to distinguish them from normal cells. Furthermore, recognition of the aberrant cell by the immune cells activates a complex interaction of mutual modulation between the immune cells, the tumor and the tumor microenvironment that may result not only in inhibition but also promotion of cancer. The deepening understanding of cancer-related immunologic processes, properties, and components has spawned exploration of more rational, mechanism-based immunologic strategies (using vaccines, antibodies, and immune modulators) for cancer prevention. This introduction to the Cancer Prevention Research immunoprevention series will attempt to review the basics of the immune response modulation as a basis for potential application to cancer immunoprevention strategies with an emphasis on vaccines. Recognizing the fast-paced research in immune response modulation, the series will cover current understandings and future directions of cancer immunoprevention research.

Cancer immunoprevention--the next frontier.

Cancer immunotherapy is a rapidly developing field, but limited in its success by a high tumor burden and immune tolerance. In contrast, immunoprevention has the potential to prevent cancer before the development of immune tolerance, and to prevent cancer recurrence in the setting of minimal residual disease. Although immunoprevention for viral-induced cancers has been successful in the setting of hepatitis B and human papillomavirus vaccination, primary prevention of nonviral-induced cancers is in its infancy. In contrast, prevention of cancer recurrence after adjuvant treatment (secondary prevention) is gaining steam. This review provides an overview of the scope of research in cancer immunoprevention over the last three years and directions for future research.

Abstract P4-11-04: Targeted vaccination against human a-lactalbumin may provide immunotherapy and immunoprevention of triple negative breast cancer

Abstract We have previously shown that a-lactalbumin vaccination mediates protection against the development of murine breast cancer in the absence of any detectable inflammatory changes in all normal non-lactating tissues examined. Based on these results, we have proposed that α-lactalbumin vaccination of healthy, cancer-free, adult women may provide safe and effective immunoprevention of breast cancer. Several issues have been raised over the past several years questioning the feasibility of applying this autoimmune strategy for breast cancer immunoprevention in the normal, healthy, cancer-free adult female population. These concerns have focused on whether adult women would be immunologically responsive to human α-lactalbumin, whether a history of lactation would create an insurmountable tolerance that would preclude generating effective immunity against α-lactalbumin, whether α-lactalbumin is immunologically available in human breast tumors, and whether expression of α-lactalbumin in normal non-breast tissues would predispose to systemic autoimmune complications. Here we provide an accumulation of several new findings that directly address these issues: 1) In vitro priming of peripheral blood mononuclear cells (PBMC) from normal healthy adult women results in frequencies of α-lactalbumin-specific interferon-gamma (IFNγ) producing T cells that are consistent with those mediating protection against breast tumor formation in mice; 2) Frequencies of IFNγ-producing T cells and the level of protection from the development of breast tumors are virtually identical whether vaccination occurs in parous mice with a history of lactation and breastfeeding or whether vaccination occurs in non-parous mice with no history of lactation; 3) ONCOMINE data base searches repeatedly show highly significant overexpression of α-lactalbumin in triple negative breast cancer (TNBC). This expression was confirmed experimentally using several methods including RT-PCR, Western blot analysis, and longitudinal visualization of α-lactalbumin gene expression during in vivo growth of human TNBC in immunodeficient mice. This in vivo visualization of α-lactalbumin gene expression was facilitated by measuring bioluminescence from growing human HCC1937 TNBC cells stably transfected with a lentivirus designed to regulate firefly luciferase expression under control of the human α-lactalbumin promoter; and 4) Evidence from the Human Protein Atlas indicates negative immunohistochemical staining for α-lactalbumin in 78 normal human tissues examined, thereby confirming the widely held view that α-lactalbumin expression in normal human tissues is confined exclusively to the lactating breast. Collectively, these findings indicate that normal, healthy, adult women are capable of mounting an immune response to human α-lactalbumin, that a history of lactation and breastfeeding has no impact on the induced immunity and the protection it provides against the development of breast cancer, and that α-lactalbumin vaccination may be most effective in providing therapy and immmunoprevention of TNBC, the most aggressive form of breast cancer and the most common variant occurring in women with BRCA1 mutations (supported by NIH R01 CA140350). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-11-04.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Preclinical HER-2 Vaccines: From Rodent to Human HER-2

Effective prevention of human cancer with vaccines against viruses, such as HBV and HPV, raises the question whether also non-virus related tumors could be prevented with immunological means. Studies in HER-2-transgenic mice showed that powerful anti-HER-2 vaccines, could almost completely prevent the onset of mammary carcinoma. Protective immune responses were orchestrated by T cells and their cytokines, and effected by antibodies against HER-2 gene product p185. Analogous findings were reported in a variety of other cancer immunoprevention systems, thus leading to the definition of oncoantigens, optimal target antigens that are causally involved in carcinogenesis and cancer progression. Prophylactic HER-2 vaccines were also effective in preventing metastasis outgrowth, indicating that concepts and approaches developed for cancer immunoprevention could prove fruitful in cancer immunotherapy as well. The availability of cancer-prone mice carrying a human HER-2 transgene is now fostering the design of novel vaccines against human p185. A further bridge toward human cancer was recently provided by novel immunodeficient models, like Rag2−/−;Il2rg−/− mice, which are permissive for metastatic spread of human HER-2+ cancer cells and can be engrafted with a functional human immune system, allowing for the first time the study of vaccines against oncoantigens to elicit human immune responses against human cancer cells in vivo.

MUC1 Vaccine for Individuals with Advanced Adenoma of the Colon: A Cancer Immunoprevention Feasibility Study

Cancer vaccines based on human tumor-associated antigens (TAA) have been tested in patients with advanced or recurrent cancer, in combination with or following standard therapy. Their immunogenicity and therapeutic efficacy has been difficult to properly evaluate in that setting characterized by multiple highly suppressive effects of the tumor and the standard therapy on the patient's immune system. In animal models of human cancer, vaccines administered in the prophylactic setting are most immunogenic and effectively prevent cancer development and progression. We report results of a clinical study that show that in patients without cancer but with a history of premalignant lesions (advanced colonic adenomas, precursors to colon cancer), a vaccine based on the TAA MUC1 was highly immunogenic in 17 of 39 (43.6%) of vaccinated individuals, eliciting high levels of anti-MUC1 immunoglobulin G (IgG) and long-lasting immune memory. Lack of response in 22 of 39 individuals was correlated with high levels of circulating myeloid-derived suppressor cells (MDSC) prevaccination. Vaccine-elicited MUC1-specific immune response and immune memory were not associated with significant toxicity. Our study shows that vaccines based on human TAAs are immunogenic and safe and capable of eliciting long-term memory that is important for cancer prevention. We also show that in the premalignant setting, immunosuppressive environment (e.g., high levels of MDSC) might already exist in some individuals, suggesting an even earlier premalignant stage or preselection of nonimmunosuppressed patients for prophylactic vaccination.

The triplex vaccine effects in mammary carcinoma: A nonlinear model in tune with SimTriplex

This paper deals with the mathematical modeling of the mammary carcinoma–immune system competition elicited by an external stimulus represented by three different protocols of the triplex vaccine [C. De Giovanni, et al., Immunoprevention of HER-2/neu transgenic mammary carcinoma through an interleukin 12-engineered allogeneic cell vaccine, Cancer Research 64 (2004) 4001–4009]. The presented model is composed of nonlinear ordinary differential equations based on parameters and cell populations. A qualitative analysis of the asymptotic behavior of the model and numerical simulations are able to depict preclinical experiments on transgenic mice in tune with the SimTriplex model [F. Pappalardo, F. Castiglione, P.L. Lollini, S. Motta, Modelling and simulation of cancer immunoprevention vaccine, Bioinformatics 21 (2005) 2891–2897]. The results are of great interest both in the applied and theoretical sciences.

Vaccines and Other Immunological Approaches for Cancer Immunoprevention

The immune system effectively prevents cancer, whereas severe immunodepression increases its incidence. Cancer immunoprevention is a strategy based on the concept that enhancement of tumor immunity in healthy individuals reduces cancer risk. It can be viewed as a kind of chemoprevention. For cancer immunoprevention, the cancer universe can be neatly divided between tumors caused - directly or indirectly - by infectious agents and all other tumors. Immunoprevention of tumors caused by infectious agents is already implemented at the population level for hepatitis B virus (HBV)-related hepatocellular carcinoma and for tumors caused by human papillomaviruses (HPV), like cervical carcinoma. Now the challenge is to develop immunological strategies to prevent the bulk ( > 80%) of human tumor burden, unrelated to infections. Both vaccines against tumor antigens and immune modulators can prevent tumor onset in cancerprone mice. These studies outlined the target antigens and the molecular and cellular mechanisms of cancer immunoprevention: a) the best target antigens are surface molecules controlling tumor growth and progression (oncoantigens); b) combinations of potent vaccines and nonspecific stimuli (adjuvants) yield the strongest protection; c) immunoprevention must start early in the natural history of tumors, before key progression events like the onset of carcinoma in situ; d) lifetime protection requires repeated boosts, to maintain a strong and steady immune response; e) antibodies and helper, rather than cytotoxic, T cells mediate long-term protection from tumor onset; f) immunoprevention can be combined with chemoprevention. The development of agents like tamoxifen, which went from cancer therapy to chemoprevention, could be a model for the translation of cancer immunoprevention from mice to humans.

Proteomic and PROTEOMEX profiling of mammary cancer progression in a HER‐2/neu oncogene‐driven animal model system

The prevention of mammary carcinoma by immunological strategies targeting the HER-2/neu receptor has proved to be effective in preclinical models. Thus, a well-characterized HER-2/neu oncogene-driven mammary carcinogenesis model was analysed by various profiling strategies following "triplex" vaccination to identify new candidate targets for breast cancer immunoprevention. 2-DE-based proteomic profiling of preneoplastic and tumour lesions versus normal and aged mammary tissue demonstrated that tumour progression was associated with an up-regulation of molecular chaperones including glucose-regulated protein (GRP)78 and of proteins favouring cell motility, which was in line with the corresponding transcriptomic profiling data. Furthermore, PROTEOMEX analyses suggested that naturally induced autoantibody responses occur during early phases of mammary cancer progression. Most of the cancer progression-induced antibodies targeted proteins of normal and preneoplastic mammary glands. However, three proteins were only recognized by sera obtained from vaccinated mice, including 2 isoforms of annexin A6. The distinct expression patterns for annexin A6 and GRP78 during tumour progression were further verified by western blot and/or immunoprecipitation. In addition, an inhibitor-mediated blockade of GRP78 expression in a model cell line caused a reduced cell growth. Thus, the proteome-based approaches applied in the murine BALB-NeuT model might indeed provide candidates for immunoprevention strategies in breast cancer.

In silico Modeling and In vivo Efficacy of Cancer-Preventive Vaccinations

Cancer vaccine feasibility would benefit from reducing the number and duration of vaccinations without diminishing efficacy. However, the duration of in vivo studies and the huge number of possible variations in vaccination protocols have discouraged their optimization. In this study, we employed an established mouse model of preventive vaccination using HER-2/neu transgenic mice (BALB-neuT) to validate in silico-designed protocols that reduce the number of vaccinations and optimize efficacy. With biological training, the in silico model captured the overall in vivo behavior and highlighted certain critical issues. First, although vaccinations could be reduced in number without sacrificing efficacy, the intensity of early vaccinations was a key determinant of long-term tumor prevention needed for predictive utility in the model. Second, after vaccinations ended, older mice exhibited more rapid tumor onset and sharper decline in antibody levels than young mice, emphasizing immune aging as a key variable in models of vaccine protocols for elderly individuals. Long-term studies confirmed predictions of in silico modeling in which an immune plateau phase, once reached, could be maintained with a reduced number of vaccinations. Furthermore, that rapid priming in young mice is required for long-term antitumor protection, and that the accuracy of mathematical modeling of early immune responses is critical. Finally, that the design and modeling of cancer vaccines and vaccination protocols must take into account the progressive aging of the immune system, by striving to boost immune responses in elderly hosts. Our results show that an integrated in vivo-in silico approach could improve both mathematical and biological models of cancer immunoprevention.

Current Issues in Tumor Immunology

The goal of tumor immunology is to understand the interactions between tumor cells and immune system, and ultimately to devise immune basedapproaches to fight cancer. We discuss here recent advances in tumor immunology and in the interaction between immunology and informatics that provide new perspectives for the development of cancer therapy. Cancer immunoprevention is a novel approach to cancer prevention through the use of vaccines and other immunological strategies to be applied before tumor onset. The efficacy of cancer immunoprevention has been demonstrated in several experimental systems, however, as frequently happens in novel approaches, cancer immunoprevention studies incorporate a large number of variables. We show here how a specifically designed lattice gas model can provide significant insight for the analysis of immune variables and the design of new biological experiments. A second approach that provides new perspectives in tumor immunology as the result of interactions between immunology and informatics is the use of DNA microarrays to investigate and monitor tumor-host relationships and modifications induced by immunopreventive and immunotherapeutic interventions. Keywords: Cancer immunoprevention, systems biology, computational models, DNA microarrays, HER-2/neu

Immunoprevention and Immunotherapy of Mammary Carcinoma

Cancer immunoprevention posits that the enhancement of immune defenses in healthy individuals could control tumor onset. Immunoprevention of viral tumors is already implemented at the population level for human hepatocellular and cervical carcinomas. Altogether, viral vaccines could prevent more than 10% of all human tumors. The big question is whether immunoprevention can be applied to nonviral tumors, including breast cancer. Promising results were obtained in preclinical models, in particular in HER-2/neu transgenic mice, which are prone to mammary carcinoma development, using vaccines against HER-2/neu oncoprotein p185. The life expectancy of vaccinated mice was more than doubled. Protective immune mechanisms elicited by effective vaccines were mainly based on helper T cell cytokines, in particular γ-interferon, and anti-p185 antibodies. The term "oncoantigens" was coined to define those antigenic molecules that, like HER-2, are indispensable for tumor growth, thus representing the best class of targets for cancer immunoprevention. The study of immunopreventive vaccines against subsequent phases of neoplastic progression showed a dramatic loss of efficacy against established mammary carcinomas, whereas the prevention of micrometastasis growth was successful. Preclinical results provide useful indications for the translation of cancer immunoprevention to humans, and useful hints for cancer immunotherapy.

Human Papillomavirus Vaccine for Cancer Prevention

Cancer immunoprevention has become synonymous with the vaccines that have been approved for the prevention of infection with highly transmissible strains of human papillomavirus (HPV) that establish chronic infection and cause cervical and other cancers.1 Although many cancers may have a viral origin,2 only a small number of viruses have been implicated as causes of human cancer. Cancer having a viral origin provides an opportunity to develop virus-specific vaccines that lower infection rates and consequently lower the incidence of cancer; this is what the HPV vaccine is expected to do for cervical cancer and what the hepatitis B vaccine has . . .