Abstract
Lymphodepletion enhances adoptive T cell transfer (ACT) therapy by activating the innate immune system via microbes released from the radiation-injured gut. Microbial LPS is a key mediator ...of lymphodepletion enhancement, but our ability to use these TLR agonists to bolster the potency of T cell-based cancer therapies remains elusive. Herein, we used LPS as a tool to address how and when to use TLR agonists to improve cancer immunotherapy. We utilized the pmel-1 melanoma mouse model. B16F10-bearing mice were lymphodepleted with 5Gy total body irradiation (TBI) and given a tripartite ACT therapy (consisting of transferred pmel-1 CD8+ T cells, vaccination with fowlpox encoding gp100, and IL-2) along with TLR4 agonist LPS. The timing of LPS administration and the requirement of individual components of the tripartite therapy were evaluated. We discovered that while exogenous administration of LPS was able to enhance CD8+ T cells’ tumor destruction, LPS treatment alone did not replace individual components of the tripartite regimen. Interestingly, administering LPS one day before ACT compromised tumor regression. Conversely, administering LPS after ACT potentiated the antitumor effectiveness of the regimen, thereby supporting the expansion of transferred CD8+ T cells over host Treg cells. Non-toxic TLR agonists MPL and CpG also improved ACT therapy. Finally, TBI preconditioning was no longer needed to regress tumors in mice depleted of host CD4+ T cells, given a tripartite ACT regimen and then treated with a TLR agonist. Collectively, our results identify how and when to administer TLR agonists to augment ACT in the absence of host preconditioning. These findings have implications for the design of next generation T cell therapies.
Abstract
We reported the antitumor activity of human Th17 cells (engineered to express a chimeric antigen receptor (CAR) that recognizes mesothelin) regresses large human mesothelioma tumors when ...infused into mice, but it remains unknown what type and what level of co-signal strength impacts their functional fate and antitumor activity. To address this question, human Th17 cells were activated with a high (3 beads: 1 T cell), medium (1:10) or low (1:100) signal via CD3-beads coated with either CD28 or ICOS agonists. We discovered Th17 cells activated with low ICOS signal were highly multifunctional (IL-17A, IFN-γ, IL-2 and IL-22) and possessed a less differentiated phenotype (high CD62L and CD45RA expression) than cells activated with a high ICOS signal. In comparison to low ICOS signal strength, Th17 cells activated with low CD28 signal strength were poorly functional and terminally differentiated. Of clinical significance, in two distinct tumor models (human mesothelioma and murine melanoma), we found that Th17 cells regressed large tumors to a better extent when primed with a low or medium ICOS signal strength compared to if they were activated with a high ICOS signal strength, or with any level of CD28 signal strength. Our data is compelling given that most ACT clinical trials use high CD3/CD28 activation to expand patients’ cells. Specifically, our work suggests the use of a low bead to T cell ratio will result in a more simple and clinically feasible method to expand highly therapeutic T cells for the clinic.
Cancer immunotherapy is one the most effective approaches for treating patients with tumors, as it bolsters the generation and persistence of memory T cells. In preclinical work, it has been reported ...that adoptively transferred CD4 super(+) and CD8 super(+) lymphocytes that secrete IL-17A (i.e., Th17 and Tc17 cells) regress tumors to a greater extent than IFN- gamma super(+)Th1 or Tc1 cells in vivo. Herein, we review the mechanisms underlying how infused Th17 and Tc17 cells regress established malignancies in clinically relevant mouse models of cancer. We also discuss how unique signaling cues-such as co-stimulatory molecules (ICOS and 41BB), cytokines (IL-12 and IL-23) or pharmaceutical reagents (Akt inhibitors, etc.)-can be exploited to bolster the therapeutic potential of IL-17 super(+) lymphocytes with an emphasis on using this knowledge to improve next-generation clinical trials for patients with cancer.
CD8
T lymphocytes mediate potent immune responses against tumor, but the role of human CD4
T cell subsets in cancer immunotherapy remains ill-defined. Herein, we exhibit that CD26 identifies three T ...helper subsets with distinct immunological properties in both healthy individuals and cancer patients. Although CD26
T cells possess a regulatory phenotype, CD26
T cells are mainly naive and CD26
T cells appear terminally differentiated and exhausted. Paradoxically, CD26
T cells persist in and regress multiple solid tumors following adoptive cell transfer. Further analysis revealed that CD26
cells have a rich chemokine receptor profile (including CCR2 and CCR5), profound cytotoxicity (Granzyme B and CD107A), resistance to apoptosis (c-KIT and Bcl2), and enhanced stemness (β-catenin and Lef1). These properties license CD26
T cells with a natural capacity to traffic to, regress and survive in solid tumors. Collectively, these findings identify CD4
T cell subsets with properties critical for improving cancer immunotherapy.
This paper reports on a small (
N=50) study of how survey respondents interpret the General Social Survey (GSS)'s “discuss important matters” name generator. The study involved concurrent think-aloud ...interviews, in which respondents were debriefed about their thought processes immediately after answering the name generator. Analyses of these responses indicate that some respondents had difficulty in specifying what was meant by the term “important matters”; sizable minorities understood the question in terms of frequency of contact or intimacy rather than in terms of specific social exchanges. Most of those interviewed said that their “important matters” had to do with personal/intimate relationships or other issues of personal life (e.g., finances, hobbies, or health), but appreciable numbers referred to work and political discussions. An interview context experiment revealed that a respondent's definition of “important matters” can be shaped by the substantive content of the preceding parts of an interview schedule. Notwithstanding these findings, the composition of the networks elicited in the study does not appear to vary substantially across interpretations of the name generator. We conclude that the name generator succeeds in measuring “core” discussion networks, though with somewhat nonspecific content. Implications for the measurement of personal networks in sample surveys are discussed.
This dissertation uses survey data on norms about the timing of life transitions to assess and explain basic tenets of life course theory. Material resources and social categories such as race and ...gender are important for these explanations. The empirical case analyzed is teenage parenthood, which is useful for studying transition norms because there are indisputably strong norms in the United States today that discourage adolescents from becoming parents. Analyses measure teenage pregnancy norms directly using the National Longitudinal Study of Adolescent Health, the National Education Longitudinal Study, and the National Pregnancy Norms Study, an original survey from a nationally representative sample of adults. I evaluate and find support for the claim that people who make life transitions too early experience worse socioeconomic outcomes than others. Life course theory asserts that these negative consequences occur because these individuals have violated societal norms about the appropriate timing of life transitions, but how these norms lead to worse outcomes is not specified. I propose and find support for one explanation: Family members who perceive strong negative norms against teenage pregnancy are less willing to provide badly needed material resources to the teenage parent. This lack of resources leads to poor socioeconomic outcomes. However, the influence of specific types of resources on education varies by the gender of the teenage parent. Additional analyses focus directly on pregnancy norms. I map norms about teenage pregnancy among adolescents and adults and show that they vary across subpopulations, including differences by race/ethnicity and socioeconomic status. Empirical evidence supports a structural explanation for this variation, in which community members' shared evaluations of the socioeconomic opportunities available to adolescents shape local norms against teenage pregnancy. This mechanism addresses an important criticism of the conception of norms by modeling change in norms across time and place. Results provide information about contemporary teenage mothers and fathers and how to help them. Findings also test and extend life course theory. By addressing criticisms of the theoretical and empirical treatment of social norms, I strive to restore transition norms to their central position in life course theory.
This dissertation uses survey data on norms about the timing of life transitions to assess and explain basic tenets of life course theory. Material resources and social categories such as race and ...gender are important for these explanations. The empirical case analyzed is teenage parenthood, which is useful for studying transition norms because there are indisputably strong norms in the United States today that discourage adolescents from becoming parents. Analyses measure teenage pregnancy norms directly using the National Longitudinal Study of Adolescent Health, the National Education Longitudinal Study, and the National Pregnancy Norms Study, an original survey from a nationally representative sample of adults. I evaluate and find support for the claim that people who make life transitions too early experience worse socioeconomic outcomes than others. Life course theory asserts that these negative consequences occur because these individuals have violated societal norms about the appropriate timing of life transitions, but how these norms lead to worse outcomes is not specified. I propose and find support for one explanation: Family members who perceive strong negative norms against teenage pregnancy are less willing to provide badly needed material resources to the teenage parent. This lack of resources leads to poor socioeconomic outcomes. However, the influence of specific types of resources on education varies by the gender of the teenage parent. Additional analyses focus directly on pregnancy norms. I map norms about teenage pregnancy among adolescents and adults and show that they vary across subpopulations, including differences by race/ethnicity and socioeconomic status. Empirical evidence supports a structural explanation for this variation, in which community members' shared evaluations of the socioeconomic opportunities available to adolescents shape local norms against teenage pregnancy. This mechanism addresses an important criticism of the conception of norms by modeling change in norms across time and place. Results provide information about contemporary teenage mothers and fathers and how to help them. Findings also test and extend life course theory. By addressing criticisms of the theoretical and empirical treatment of social norms, I strive to restore transition norms to their central position in life course theory.
Trust is a central component of effective patient-physician relationships (Barber 1983; Mechanic and Schlesinger 1996). It has been shown to influence a variety of important processes and outcomes, ...including communication between patients and their physicians, patients' satisfaction, compliance and adherence to therapeutic regimens, and continuity of the relationship. No single theoretical framework lends itself readily to the study of the problem of trust in patient-physician relationships. Therefore, we chose an inductive strategy for modeling trust, based on qualitative data collected in focus groups and interviews. Patients identified three major categories of determinants of trust: (1) characteristics and experiences with the health care context and setting, (2) characteristics and behaviors of the physician, and (3) characteristics and behaviors of the patient. We then tested this model using data from a large nationally representative sample, the Community Tracking Study Household Survey (Center for Studying Health System Change 2001). We estimated a series of nested ordinal probit models of trust using maximum likelihood. We found that the factors suggested by the qualitative analysis were in fact fairly good predictors of patient trust in this sample (psuedo-R2=.18). All of the factors included in the model were significant at the p<.05 levels, with the exception of some racial/ethnic categories. Physician behaviors and characteristics (listening, explaining, referring, being influenced by insurance rules and thoroughness of examination) affected patient trust. The variables measuring utilization, continuity of care, and patients' subjective perceptions of care (satisfaction with health care and physician and physician behaviors and attitudes) were particularly important. We found it useful in integrating our qualitative and quantitative findings to view patients and physicians as interdependent social actors involved in reciprocal, exchange relationships (Cook 1987) with two theoretically relevant features: (1) substantial asymmetries in power and dependence, and (2) the embeddedness of the exchange relationship in complex networks and institutional arrangements.
Cancer immunotherapy is one the most effective approaches for treating patients with tumors, as it bolsters the generation and persistence of memory T cells. In preclinical work, it has been reported ...that adoptively transferred CD4^sup +^ and CD8^sup +^ lymphocytes that secrete IL-17A (i.e., Th17 and Tc17 cells) regress tumors to a greater extent than IFN-γ^sup +^Th1 or Tc1 cells in vivo. Herein, we review the mechanisms underlying how infused Th17 and Tc17 cells regress established malignancies in clinically relevant mouse models of cancer. We also discuss how unique signaling cues--such as co-stimulatory molecules (ICOS and 41BB), cytokines (IL-12 and IL-23) or pharmaceutical reagents (Akt inhibitors, etc.)--can be exploited to bolster the therapeutic potential of IL-17^sup +^ lymphocytes with an emphasis on using this knowledge to improve next-generation clinical trials for patients with cancer.
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