Overcoming Resistance to anti-PD1 Treatment in Cancer Immunotherapy

In modern medical discussions, cancer's global burden remains a significant challenge, with around 10 million cancer-related deaths and an estimated 19.3 million new cases reported each year, as forecasted by GLOBOCAN 2020. Undoubtedly, cancer continues to exert a significant toll on public health, posing a substantial impediment to advancing global life expectancy. Amidst this complex landscape, tumor immunotherapy has emerged as a pivotal strategy in cancer treatment. Acknowledged as one of the foundational pillars of cancer therapy by the American Association for Cancer Research (AACR) in 2019, tumor immunotherapy, alongside surgery, chemotherapy, radiation, and molecularly targeted medicines, represents a beacon of hope in the fight against cancer.

At the forefront of tumor immunotherapy lies the concept of stimulating or augmenting the body's immune system to eliminate tumors. However, tumors often employ sophisticated mechanisms to evade immunotherapy, presenting a significant challenge in treatment efficacy. Central to this evasion is the programmed death receptor 1/programmed death receptor-ligand 1 (PD-1/PD-L1) pathway, exerting a profound influence on immune tolerance and evasion within the tumor microenvironment (TME). PD-1 receptors, found on activated T cells, interact with PD-L1 receptors expressed on cancer cells, thereby dampening the function of cytotoxic T-lymphocytes (CTLs) and facilitating immune evasion.

Despite the promise of tumor immunotherapy, a notable proportion of patients encounter primary or acquired resistance to treatment, characterized by unresponsiveness or recurrence following anti-PD-1/PD-L1 therapy. This resistance underscores the intricate interplay between tumors and the immune system, with PD-1/PD-L1-mediated immune escape mechanisms playing a pivotal role. These mechanisms encompass the suppression of T cell activity, promotion of tumor cell evasion from immune recognition, and dysregulation of specific immunosuppressive proteins.

In light of these challenges, a comprehensive understanding of the factors contributing to immunotherapeutic resistance is imperative for advancing anti-tumor immunotherapy. In this context, individualized medication tailored to maximize patient benefit represents a crucial frontier in cancer treatment. This article delves into the factors associated with immunotherapeutic resistance stemming from tumor immune evasion during PD-1/PD-L1 inhibitor therapy. Furthermore, it explores potential strategies to overcome such resistance, providing a robust evidence base for the future of precision medicine in cancer.

The PD-1/PD-L1 pathway orchestrates immune evasion within tumors by exerting inhibitory effects on immune cell function, thereby impeding the body's ability to mount an effective anti-tumor immune response. Effective immune checkpoint inhibitors (ICIs) hold the potential to disrupt these aberrant interactions, restoring the functionality of tumor-specific T cells and enabling recognition and eradication of tumors. PD-1, a key player in this pathway, is predominantly expressed on activated T cells, while its ligands, PD-L1 and PD-L2, are expressed on various immune and tumor cells.

Paradoxically, while the PD-1/PD-L1 pathway serves to maintain immune homeostasis and prevent autoimmune diseases, its activation within the TME promotes tumor immune evasion. Upon encountering tumor antigens, T cells express PD-1, leading to the upregulation of PD-L1 by tumor cells in response to inflammatory mediators. This interaction induces downstream signaling events that inhibit T cell activation, culminating in immune evasion by the tumor.

The effectiveness of PD-1/PD-L1 immunotherapy hinges on overcoming the myriad mechanisms through which tumors evade immune surveillance. Enhancing T cell proliferation, cytotoxicity, and infiltration into the tumor microenvironment represents a promising avenue for promoting anti-tumor immunity. However, the development of immunotherapeutic resistance underscores the need for a multifaceted approach that addresses the complex interplay between tumors and the immune system.

Exploring Factors Influencing Immunotherapy Resistance

Immunotherapy has revolutionized cancer treatment, offering new hope for patients with various malignancies. However, not all patients respond favorably to immunotherapy, and understanding the factors contributing to treatment resistance is crucial for improving patient outcomes. Immunotherapy resistance can be broadly categorized into primary and acquired resistance, each driven by distinct molecular mechanisms.

Primary Resistance: This occurs when tumors fail to respond to initial immunotherapy treatment. Several factors contribute to primary resistance, including impaired tumor-associated antigen presentation and alterations in intracellular molecular pathways within tumors. For example, epigenetic modifications in tumor DNA can disrupt antigen processing and presentation, while persistent activation of certain signaling pathways reduces immune cell infiltration into the tumor microenvironment (TME). Additionally, immunosuppressive cells within the TME secrete inhibitory cytokines, such as interleukin 10 (IL-10) and transforming growth factor β (TGF-β), further hindering the immune response.

Acquired Resistance: This occurs when tumors initially respond to immunotherapy but later progress or reappear. Acquired resistance can arise due to the emergence of new tumor cell strains that are resistant to treatment. Furthermore, the compensatory upregulation of immune checkpoints, such as T cell immunoglobulin mucin 3 (TIM-3) and lymphocyte activation gene protein 3 (LAG-3), after treatment can lead to increased expression of other immune surveillance pathways, contributing to drug resistance.

Understanding the mechanisms underlying immunotherapy resistance is essential for developing strategies to overcome it. Effective immunotherapy relies on three fundamental conditions: T cell recognition of tumor antigens, T cell migration and infiltration into tumors, and activation of T cells to trigger tumor cell killing. Disruption of any of these factors can lead to T cell dysfunction and immune evasion by tumors.

Tumor Antigen Deletion and Recognition Disorders: Tumor antigens must be presented to T cells for effective immunotherapy. However, tumors can evade immune detection by downregulating major histocompatibility complex I (MHC-I) expression, which is crucial for antigen presentation to CD8+ T cells. Mutations or deficiencies in proteins like beta-2-microglobulin (B2M) can lead to reduced HLA-I expression, impairing antigen presentation and promoting immune escape. Similarly, alterations in MHC-II expression can limit antigen presentation and promote immune evasion.

T Cell Dysfunction: Once T cells recognize tumor antigens, they must undergo activation and infiltration into tumors to exert their anti-tumor effects. However, the upregulation of immune checkpoints like PD-1/PD-L1 can inhibit T cell activation and proliferation, leading to immune suppression. Additionally, abnormalities in signaling pathways, such as the PI3K-AKT pathway, can impair T cell function and infiltration into tumors, further contributing to immunotherapy resistance.

Increase in Immunosuppressive Cells: The tumor microenvironment is often enriched with immunosuppressive cells, such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), which inhibit anti-tumor immune responses. Tregs suppress immune function by releasing inhibitory molecules and competing with effector T cells for resources. Similarly, MDSCs and TAMs promote immune evasion by inhibiting T cell function and promoting tumor growth. Targeting these immunosuppressive cells may enhance the efficacy of immunotherapy and overcome resistance.

Drug Resistance due to Changes in PD-L1 Expression: The PD-1/PD-L1 pathway is a key target for immunotherapy, but alterations in PD-L1 expression can lead to resistance. Tumor cells can adaptively increase PD-L1 levels to evade immune attack, while low PD-L1 expression can also result in ineffective immunotherapy. Additionally, abnormal signaling pathways and mutations can further modulate PD-L1 expression, contributing to treatment resistance.

Other Factors in Immunotherapy Resistance: Metabolic abnormalities, alterations in the gut microbiota, and changes in DNA methylation can also impact immunotherapy response. Dysregulated metabolism in tumor cells can create an immunosuppressive microenvironment, promoting immune escape. Similarly, alterations in the gut microbiota have been linked to variations in immunotherapy effectiveness, highlighting the potential role of the microbiome in treatment resistance. Furthermore, changes in DNA methylation patterns can affect tumor antigen presentation and immune cell function, influencing immunotherapy response.

In summary, immunotherapy resistance is a complex phenomenon driven by various factors within the tumor microenvironment and the host's immune system. By understanding these mechanisms, researchers can develop targeted strategies to overcome resistance and improve the efficacy of immunotherapy for cancer patients. Continued research into these factors is essential for advancing cancer treatment and ultimately improving patient outcomes.

Enhancing Immune Cell Function: A Multifaceted Approach

Immunogenic Cell Death (ICD) Induction:

Immunogenic cell death (ICD) stands as a potent mechanism to bolster tumor immunogenicity, thus enhancing therapeutic outcomes. Strategies employing ICD induction, such as anthracycline-induced ICDs, have exhibited promising results by augmenting immunotherapeutic responses. Combining ICD inducers with PD-1/PD-L1 inhibition represents a synergistic approach to overcome resistance and elevate treatment efficacy. Furthermore, cancer vaccines formulated with tumor-specific antigens and adjuvants offer a viable avenue to stimulate antigen-specific immune responses, thereby potentiating the action of PD-1/PD-L1 inhibitors. Clinical trials exploring mRNA cancer vaccines in tandem with PD-1/PD-L1 inhibitors have demonstrated encouraging outcomes across various tumor types, underscoring the potential of this combinatorial approach.

Co-stimulatory Signaling Enhancement:

Amplifying co-stimulatory signaling pathways is imperative for bolstering T cell activation and combating immunotherapy resistance. Strategies targeting non-specific co-stimulatory molecules, such as B7 and CD28, hold promise in this regard. Inhibitors of apoptosis proteins (IAPs) antagonists and histone deacetylase 6 (HDAC6) inhibitors emerge as pivotal players in enhancing co-stimulatory signaling. Preclinical research indicates that IAP antagonists synergize with conventional chemotherapeutic drugs and immune checkpoint inhibitors, showcasing their potential in overcoming resistance. Similarly, HDAC6 inhibitors exhibit the capacity to enhance co-stimulatory molecule expression and activate T cell anti-tumor activity, thereby augmenting the efficacy of PD-1/PD-L1 blockade therapy.

Tumor Microenvironment (TME) Modulation:

The TME exerts profound influence on immune responses and therapeutic outcomes, necessitating targeted interventions to overcome resistance. Strategies aimed at converting "cold tumors" into "hot tumors" by inducing immunogenicity and T cell infiltration hold promise in this endeavor. Activation of the cGAS-STING pathway and manipulation of the TME through radiotherapy have shown efficacy in enhancing T cell infiltration and restoring immune responses. Furthermore, targeting immunosuppressive cells within the TME, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), represents a crucial avenue for overcoming resistance. Various therapeutic modalities, including bispecific antibodies, chemokine modulation, and metabolic interventions, offer promising strategies to mitigate immunosuppression and enhance anti-tumor immunity.

Predictive Biomarkers of Efficacy: Guiding Precision Medicine

CD8+ T Cell Infiltration and PD-L1 Expression:

Characterizing immune indicators, such as CD8+ T cell infiltration and PD-L1 expression, serves as a cornerstone for predicting immunotherapy response. Elevated CD8+ T cell infiltration correlates positively with treatment efficacy across diverse tumor types, highlighting its utility as a predictive biomarker. Likewise, PD-L1 expression levels hold prognostic significance, with high expression levels associated with favorable treatment outcomes. Leveraging these biomarkers enables precision medicine approaches to optimize treatment selection and improve patient stratification.

Emerging Predictors: IFNs and Tumor Mutational Load (TMB):

Emerging biomarkers, including immune-associated interferons (IFNs) and tumor mutational load (TMB), offer novel avenues for predicting treatment response. IFNs play a pivotal role in modulating immune responses and sensitizing tumors to immunotherapy. Elevated TMB levels correlate with improved treatment response, underscoring its potential as a predictive biomarker. These emerging predictors enrich our understanding of treatment response dynamics and inform personalized therapeutic strategies.

Targeting the Tumor Microenvironment: A Paradigm Shift in Immunotherapy

TME Modulation: A Multifaceted Approach:

The TME serves as a critical determinant of treatment efficacy, necessitating targeted interventions to overcome resistance mechanisms. Strategies targeting metabolic pathways, microbiota dysbiosis, and immune-microbiota interactions offer novel avenues for TME modulation. By disrupting immunosuppressive signals and enhancing immune cell function, targeted TME interventions hold promise in augmenting immunotherapy outcomes and overcoming resistance.

Pioneering Targeted Therapies for Enhanced Efficacy

The pursuit of targeted therapeutics heralds a new era in oncology, offering renewed hope for overcoming immunotherapy resistance. By integrating multifaceted approaches that enhance immune cell function, leverage predictive biomarkers, and modulate the TME, we strive to maximize treatment efficacy and improve patient outcomes. The convergence of precision medicine and immunotherapy holds immense potential in revolutionizing cancer care and ushering in an era of personalized therapeutic interventions. As we continue to unravel the complexities of immunotherapy resistance, the quest for innovative treatment strategies remains steadfast, driven by the shared commitment to combatting cancer and improving lives.

Conclusion

Tumors present a complex challenge due to their heterogeneity and genetic instability, which complicates treatment strategies. While PD-1/PD-L1 immunotherapy has shown promise, resistance to these medications is a significant issue. The evasion of tumor cells from immunotherapy, facilitated by PD-1/PD-L1, is closely associated with resistance. Here, we explore the contributing factors to PD-1/PD-L1 blockade resistance and examine current strategies and potential molecular targets for coping with this challenge.

In general, tumor cells evade immunotherapy by downregulating PD-L1 expression or modulating immune cell infiltration in the tumor microenvironment (TME). Additionally, the increase in immunosuppressive cells within the TME inhibits T cell activation, undermining the body's response to immunotherapy. Metabolic dysregulation, alterations in microbiota, and tumor genetic heterogeneity are all implicated in PD-1/PD-L1 immunotherapy resistance. Therapeutic agents targeting the PD-1/PD-L1 pathway aim to restore T cell function, aiding the immune system in combating cancer. Moreover, resistance can involve molecular targets such as IL10 and IFN-γ, along with other inflammatory mediators like IL-6 and IL-17, providing potential targets for combination immunotherapy.

While elevated PD-1/PD-L1 expression is generally associated with a positive prognosis, tumors can develop resistance by dynamically enhancing PD-L1 expression in response to treatment. Optimal treatment strategies are still being refined, as PD-L1 levels do not always correlate with treatment efficacy.

Partial resistance to PD-1 blockade may involve the release of PD-L1 through Exo. Currently, there are no direct therapeutic agents targeting Exo PD-L1, but strategies such as interfering with Exo signaling or inhibiting Exo biosynthesis are being explored to enhance anti-PD-1/PD-L1 efficacy. Further research is needed to optimize these strategies for improved therapeutic outcomes and safety. While existing biomarkers aid in prediction, additional molecular markers such as alpha-fetoprotein, microRNAs, and DNA methylation levels may enhance predictive accuracy.

Despite the discovery of targeted therapies, treatment optimization must be tailored to individual patients. The future of tumor immunotherapy lies in individualized approaches, including immune cell therapy, personalized tumor vaccines, and peptide vaccines. Understanding the complex interplay between immunotherapy resistance and PD-1/PD-L1-mediated tumor immune escape is crucial for developing effective treatments and overcoming drug resistance. Enhanced comprehension of these mechanisms and the development of innovative treatment strategies are essential steps toward improving tumor immunotherapy efficacy.