The story began in February 2022, when the patient was admitted to a hospital with hoarseness and coughing up blood. Imaging and pathology confirmed left lung adenocarcinoma with brain metastases, classified as stage IV under the American Joint Committee on Cancer TNM staging system, eighth edition. His tumor biology was aggressive: immunohistochemistry revealed a Ki-67 proliferation index of 70 percent and a PD-L1 tumor proportion score of 90 percent, while genetic testing showed wild-type EGFR and ALK. Because his tumor expressed PD-L1 so strongly, he was enrolled in a randomized, double-blind, placebo-controlled trial testing an anti-TIGIT antibody alongside atezolizumab for advanced non-small cell lung cancer. On March 21, 2022, he completed one cycle of atezolizumab at 1,200 milligrams plus the anti-TIGIT antibody or placebo at 600 milligrams, both intravenously, without immediate complications.

Less than a month later, the trouble started. The patient developed fatigue, facial swelling, and a rash. Laboratory tests on April 18, 2022 revealed elevated liver enzymes, with alanine aminotransferase at 71.9 units per liter and aspartate aminotransferase at 193.1 units per liter, along with abnormal cardiac markers including cardiac troponin T at 0.036 nanograms per milliliter, creatine kinase-MB at 41.8, and myoglobin at 1,371 nanograms per milliliter. Doctors at the first hospital suspected immune-related myocarditis, hepatitis, and secondary adrenal insufficiency, stopped the immunotherapy, and started methylprednisolone at 60 milligrams twice daily, later escalating the dose. Follow-up was disrupted by the COVID-19 pandemic, and by late May the patient had worsening chest discomfort, severe facial and neck edema, and a widespread rash. Neck computed tomography showed tonsillitis and inflammation of the parotid and submandibular glands compressing the trachea enough to require intubation. His platelet count then crashed to 15 times 10 to the ninth per liter, and his liver function deteriorated further.

When the patient reached the team at Zhongshan Hospital, Fudan University, the physicians conducted a systematic re-evaluation of each suspected immune-related adverse event. Cardiac magnetic resonance imaging with enhancement revealed scattered patchy enhancement in the left ventricular lateral wall and linear delayed enhancement in the subepicardium of the inferoposterior wall, findings strongly suggestive of grade 3 checkpoint inhibitor myocarditis, with a left ventricular ejection fraction of 50 percent. Pulmonary embolism and worsening of pre-existing cardiovascular disease were ruled out. A liver biopsy showed mild sinusoidal congestion, subtle inflammatory infiltration, bile stasis, hepatocyte swelling, and focal necrosis, consistent with grade 2 immune-related hepatic injury in the absence of liver metastases, viral hepatitis, or autoimmune disease. A bone marrow biopsy demonstrated poor maturation of megakaryocytes without tumor invasion, supporting grade 4 immune-mediated thrombocytopenia. Finally, the combination of widespread muscle soreness, facial and periorbital swelling, elevated creatine kinase dominated by the skeletal muscle fraction, and impaired self-care pointed to grade 4 dermatomyositis, with the MDA5 antibody testing negative.

Treatment was aggressive and multidisciplinary. The patient received intravenous methylprednisolone at 160 milligrams daily for five days, together with intravenous immunoglobulin at 20 grams daily for seven days, plus hepatoprotective, gastric-protective, anti-infective, and nutritional support. Cardiac troponin stabilized and platelet counts rose significantly, but liver enzymes and bilirubin continued climbing, prompting the addition of tofacitinib, a Janus kinase inhibitor, at 5 milligrams per day starting June 11, 2022. Liver function and the rash gradually improved, allowing tapering of the methylprednisolone from June 19 onward. After discharge, steroids were tapered weekly, and tofacitinib was stopped when the oral dose reached 30 milligrams per day. Yet each attempt to withdraw immunosuppression backfired: at 10 milligrams of methylprednisolone, pruritic rashes reappeared on the right lower limb with rising creatine kinase-MB, requiring a five-day course of intravenous methylprednisolone at 40 milligrams. A second taper attempt triggered worsening rashes and elevations in troponin, creatine kinase, and creatine kinase-MB, and tofacitinib was reintroduced.

Because the dermatomyositis persisted and multiple organ systems remained involved, steroid withdrawal proved impossible. The team settled on a long-term maintenance regimen of low-dose methylprednisolone, 5 milligrams every other day, plus tofacitinib 5 milligrams twice daily. To date, the patient has improved markedly, with rashes substantially alleviated, normal liver function, and normalization of most cytokines and cardiac markers. In a striking twist, he has received no anti-tumor therapy since the adverse events began, yet his tumor remained stable for a long period, a phenomenon the authors note with interest, before follow-up chest computed tomography on December 13, 2024 showed localized recurrence.

The clinical course illustrates why checkpoint inhibitor myocarditis demands such vigilance. Although cardiac involvement is among the rarer immune-related adverse events, it carries a mortality rate of 25 to 50 percent, with rapid onset, atypical symptoms, and swift progression. Risk factors include combination checkpoint blockade, concurrent cardiotoxic cancer drugs, and pre-existing cardiovascular disease. High-dose corticosteroids are the cornerstone of treatment, and guidelines such as those from the National Comprehensive Cancer Network recommend permanent discontinuation of checkpoint inhibitors, electrocardiographic and echocardiographic monitoring, and pulsed methylprednisolone for three to five days in grade 3 cases, followed by tapering over four to six weeks. When patients resist steroid pulse therapy, guidelines suggest adding a chemotherapeutic or biological agent plus immunoglobulins, with antithymocyte globulin or alemtuzumab offering potential advantages. In this case, the combination of immunoglobulin and tofacitinib alongside steroids appeared to play a critical role in achieving disease control.

The hepatic and hematological complications add further lessons. Immune-related liver injury typically emerges six to fourteen weeks after starting checkpoint inhibitors, with an incidence around 8.4 percent in one cited cohort, and patients receiving dual immune therapy are more susceptible to hepatotoxicity. Steroid dosing for hepatitis is generally lower than for myocarditis, scaled to the grade of liver dysfunction, and the pathological basis, autoimmune cells attacking normal hepatocytes, mirrors that of cardiac injury. The authors also raise an unresolved question: when patients are already on high-dose steroids and immunoglobulins, should standard hepatoprotective drugs be continued? Current guidelines offer little guidance on this point. Immune thrombocytopenia, meanwhile, occurs in fewer than 1 percent of checkpoint inhibitor recipients, usually within the first twelve weeks, and remains a diagnosis of exclusion. Because thrombocytopenia is common in cancer patients, clinicians must systematically rule out infection, tumor progression, and drug effects before attributing it to immunotherapy, as the team did here through bone marrow biopsy and careful history-taking.

What makes this case scientifically valuable is its rarity and its implications for the next generation of immunotherapy. TIGIT, a co-inhibitory receptor expressed on T cells and natural killer cells that competes with the costimulatory molecule CD226 for the ligands CD155 and CD112, has shown synergistic anti-tumor effects with PD-1 and PD-L1 blockade in preclinical studies, and trials of tiragolumab combinations have generally reported acceptable safety profiles. Yet this patient experienced four simultaneous, severe immune-related adverse events after a single treatment cycle, underscoring that combining checkpoints acting on different pathways can amplify loss of immune tolerance in unpredictable ways. The authors emphasize that multisystemic immune-related adverse events tend to appear early and progress rapidly, that glucocorticoids remain the core therapy, and that severe cases may require intravenous immunoglobulin, plasma exchange, or additional immunomodulatory drugs such as tofacitinib. For oncologists deploying anti-TIGIT and anti-PD-L1 combinations in trials and clinics, the message is clear: early recognition, precise diagnosis across organ systems, and prompt multidisciplinary intervention can mean the difference between catastrophe and recovery.

Subject of Research: Multisystemic immune-related adverse events from anti-PD-L1 and anti-TIGIT combination immunotherapy in lung adenocarcinoma

Article Title: Management of multisystemic irAEs associated with atezolizumab/tiragolumab combination therapy in a patient with lung adenocarcinoma: case report and review

Article References: Zhang, S., Zhang, N., Lin, J., Zhao, L., Jin, H., Gao, D., Ji, Z., Liu, Q., Ai, L., & Yu, Y. (2025). Management of multisystemic irAEs associated with atezolizumab/tiragolumab combination therapy in a patient with lung adenocarcinoma: case report and review. Clinical Cancer Bulletin, 4(1), Article 6. https://doi.org/10.1007/s44272-025-00034-2

Image Credits: AI Generated

DOI: 10.1007/s44272-025-00034-2

Keywords: immune checkpoint inhibitors, atezolizumab, tiragolumab, TIGIT, PD-L1, myocarditis, immune-related adverse events, lung adenocarcinoma, dermatomyositis, thrombocytopenia, hepatitis, tofacitinib

Immune checkpoint inhibitors revolutionize cancer treatment by harnessing the immune system’s ability to target tumor cells more effectively than conventional chemotherapy. Notably, ICIs exhibit superior tolerability profiles in elderly patients, a cohort traditionally vulnerable to the toxicities of cytotoxic agents. Nonetheless, the clinical application in the elderly is hampered by their underrepresentation in pivotal clinical trials, creating critical gaps in understanding the spectrum and severity of immune-related adverse events (irAEs) linked to ICIs, particularly as they may vary between different tumor types.

Addressing this knowledge void, a pioneering retrospective observational study spearheaded by Peking University Cancer Hospital analyzed real-world data from 407 elderly patients aged 70 years and above, all having undergone at least two cycles of ICI therapy. This cohort included 261 patients with gastrointestinal tumors and 146 with lung cancer, enrolled between January 2016 and February 2022. By applying a sophisticated 2:1 propensity score matching approach, the investigators meticulously balanced covariates such as sex, smoking history, Eastern Cooperative Oncology Group (ECOG) performance status, and concomitant treatment modalities, culminating in two well-matched groups: 197 elderly patients with GI tumors and 133 with lung cancer.

The study’s primary endpoint focused on the incidence of any-grade irAEs, which were systematically classified according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, while a secondary analysis explored organ-specific toxicity profiles. These rigorous methodologies represent a significant advancement in carefully delineating the nuanced safety landscape of ICIs in elderly populations afflicted with distinct tumor types, an area previously obscured by heterogeneous clinical trial data.

Intriguingly, the results revealed a tangible disparity in the incidence of immune-related toxicities between the two cohorts. The overall irAE occurrence was 52.6% across the study population, yet lung cancer patients exhibited a notably higher incidence at 61.0%, compared to 47.9% in GI tumor patients—a statistically significant difference underscored by a p-value of 0.013. This trend persisted post-propensity score matching, with lung cancer group irAEs slightly higher (61.7% vs. 50.8%, though just shy of statistical significance at p=0.056), and a pronounced difference in mild-to-moderate (grade 1-2) irAEs favoring lung cancer patients (52.6% vs. 37.1%, p=0.006).

Diving deeper into the organ-specific irAEs, the study uncovered distinctive patterns reflective of tumor biology and host immune interaction. Cutaneous toxicities emerged as the most prevalent irAE, affecting 23.8% of the entire cohort, but displayed a significant predilection for GI tumor patients, with a 28.7% incidence relative to 15.1% among lung cancer patients (p=0.002). Conversely, thyroid dysfunction—characterized by autoimmune thyroiditis or hypothyroidism—surfaced as a prominent adverse event within the lung cancer group, occurring in 28.1% of patients versus 11.9% in those with GI tumors (p < 0.001). Other organ systems, including hepatobiliary toxicity, cytopenias, and pneumonitis, showed no statistically significant differences between the groups, suggesting a degree of tumor-specific immune modulation confined to particular organ toxicities.

These findings illuminate a complex interplay between tumor microenvironment heterogeneity and systemic immune responses modulated by ICIs, which may be further influenced by gut microbiota compositions, especially relevant in GI cancers. The gut microbiome’s modulatory role in immune homeostasis and response to checkpoint blockade introduces a mechanistic hypothesis for the observed differential patterns of irAEs. Understanding such interactions could pave the way for novel predictive biomarkers and tailored prophylactic approaches to manage toxicity profiles across diverse oncologic populations.

Importantly, this research stands as the inaugural large-scale real-world investigation to dissect tumor-specific immune toxicities in an elderly cohort, filling a crucial evidence gap left by randomized controlled trials. The clinical implications are profound: practitioners should adopt vigilant monitoring protocols for thyroid dysfunction in elderly lung cancer patients receiving ICIs and simultaneously be alert for cutaneous irAEs in those battling GI tumors. Tailoring surveillance and management strategies according to tumor type could mitigate adverse effects, enhance patient quality of life, and potentially improve treatment adherence.

While these insights herald a new frontier in geriatric oncology, the study’s limitations must be acknowledged. Being a single-center retrospective analysis confines the generalizability of the findings, and the absence of longitudinal data correlating irAEs with therapeutic efficacy leaves critical questions unanswered. Future multicenter prospective studies integrating robust biomarker analyses and longitudinal follow-up are indispensable to validate and expand upon these foundational observations.

Led by Dr. Yuyan Wang, a distinguished thoracic oncologist at Peking University Cancer Hospital, this study underscores an era where clinical research is increasingly responsive to the nuances of elderly cancer care. Dr. Wang’s expertise in thoracic oncology and her research into tumor microenvironment dynamics and molecular resistance mechanisms have been instrumental in shaping this pioneering investigation. Supported by multiple institutional and national grants, the collaborative endeavor reflects a commitment to addressing the unmet needs of an aging oncologic population.

Collectively, these findings advance our understanding of immunotherapy’s safety profile among elderly patients with lung and GI cancers, reinforcing the necessity for tumor-specific and patient-centered approaches. They evoke critical questions about the immunobiology underpinning differential irAE manifestations and herald an opportunity for precision medicine to extend beyond efficacy into toxicity management. As the medical community grapples with rising cancer burdens in the elderly, such research offers hope for improved outcomes through personalized, immune-guided treatment strategies.

In summary, this landmark real-world study elucidates the heterogeneous landscape of immune-related adverse events in elderly patients treated with ICIs for gastrointestinal and lung cancers. The discernible variation in both incidence and organ-specific toxicity emphasizes the importance of tumor biology in shaping immune responses and adverse event profiles. Enhanced surveillance tailored to tumor site—especially for thyroid dysfunction in lung cancer and skin toxicities in GI cancers—may optimize immunotherapy’s risk-benefit balance and usher in refined standards of care for an increasingly vulnerable patient population.

Subject of Research: People

Article Title: Immune-related adverse events between elderly patients with gastrointestinal and lung cancers: A real-world study

News Publication Date: 3-Apr-2026

Web References: DOI link

References: DOI: 10.1097/CM9.0000000000004069

Image Credits: Chinese Medical Journal

Keywords: Immune checkpoint inhibitors, elderly cancer patients, gastrointestinal cancer, lung cancer, immune-related adverse events, toxicity profiles, tumor microenvironment, propensity score matching, thyroid dysfunction, skin toxicity, real-world study, immunotherapy